Pyridazinone derivatives

ABSTRACT

Compounds of the formula (I) in which D, R 1 , R 2 , R 3 , R 4  have the meanings indicated in Claim  1 , are inhibitors of tyrosine kinases, in particular of Met kinase, and can be employed, inter alia, for the treatment of tumors.

BACKGROUND OF THE INVENTION

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

The present invention relates to compounds and to the use of compoundsin which the inhibition, regulation and/or modulation of signaltransduction by kinases, in particular tyrosine kinases and/orserine/threonine kinases, plays a role, furthermore to pharmaceuticalcompositions which comprise these compounds, and to the use of thecompounds for the treatment of kinase-induced diseases.

In particular, the present invention relates to compounds and to the useof compounds in which the inhibition, regulation and/or modulation ofsignal transduction by Met kinase plays a role.

One of the principal mechanisms by which cellular regulation is effectedis through the transduction of extracellular signals across the membranethat in turn modulate biochemical pathways within the cell. Proteinphosphorylation represents one course by which intracellular signals arepropagated from molecule to molecule resulting finally in a cellularresponse. These signal transduction cascades are highly regulated andoften overlap, as is evident from the existence of many protein kinasesas well as phosphatases. Phosphorylation of proteins occurspredominantly at serine, threonine or tyrosine residues, and proteinkinases have therefore been classified by their specificity ofphosphorylation site, i.e. serine/threonine kinases and tyrosinekinases. Since phosphorylation is such a ubiquitous process within cellsand since cellular phenotypes are largely influenced by the activity ofthese pathways, it is currently believed that a number of disease statesand/or diseases are attributable to either aberrant activation orfunctional mutations in the molecular components of kinase cascades.Consequently, considerable attention has been devoted to thecharacterisation of these proteins and compounds that are able tomodulate their activity (for a review see: Weinstein-Oppenheimer et al.Pharma. &. Therap., 2000, 88, 229-279).

The role of the receptor tyrosine kinase Met in human oncogenesis andthe possibility of inhibition of HGF (hepatocyte growth factor)dependent Met activation are described by S. Berthou et al. in Oncogene,Vol. 23, No. 31, pages 5387-5393 (2004). The inhibitor SU11274 describedtherein, a pyrrole-indoline compound, is potentially suitable forcombating cancer.

Another Met kinase inhibitor for cancer therapy is described by J. G.Christensen et al. in Cancer Res. 2003, 63(21), 7345-55.

A further tyrosine kinase inhibitor for combating cancer is reported byH. Hov et al. in Clinical Cancer Research Vol. 10, 6686-6694 (2004). Thecompound PHA-665752, an indole derivative, is directed against the HGFreceptor c-Met. It is furthermore reported therein that HGF and Met makea considerable contribution to the malignant process of various forms ofcancer, such as, for example, multiple myeloma.

The synthesis of small compounds which specifically inhibit, regulateand/or modulate signal transduction by tyrosine kinases and/orserine/threonine kinases, in particular Met kinase, is thereforedesirable and an aim of the present invention.

It has been found that the compounds according to the invention andsalts thereof have very valuable pharmacological properties while beingwell tolerated.

The present invention specifically relates to compounds of the formula Iwhich inhibit, regulate and/or modulate signal transduction by Metkinase, to compositions which comprise these compounds, and to processesfor the use thereof for the treatment of Met kinase-induced diseases andcomplaints, such as angiogenesis, cancer, tumour formation, growth andpropagation, arteriosclerosis, ocular diseases, such as age-inducedmacular degeneration, choroidal neovascularisation and diabeticretinopathy, inflammatory diseases, arthritis, thrombosis, fibrosis,glomerulonephritis, neurodegeneration, psoriasis, restenosis, woundhealing, transplant rejection, metabolic diseases and diseases of theimmune system, also autoimmune diseases, cirrhosis, diabetes anddiseases of the blood vessels, also instability and permeability and thelike in mammals.

Solid tumours, in particular fast-growing tumours, can be treated withMet kinase inhibitors. These solid tumours include monocytic leukaemia,brain, urogenital, lymphatic system, stomach, laryngeal and lungcarcinoma, including lung adenocarcinoma and small-cell lung carcinoma.

The present invention is directed to processes for the regulation,modulation or inhibition of Met kinase for the prevention and/ortreatment of diseases in connection with unregulated or disturbed Metkinase activity. In particular, the compounds of the formula I can alsobe employed in the treatment of certain forms of cancer. The compoundsof the formula I can furthermore be used to provide additive orsynergistic effects in certain existing cancer chemotherapies, and/orcan be used to restore the efficacy of certain existing cancerchemotherapies and radiotherapies.

The compounds of the formula I can furthermore be used for the isolationand investigation of the activity or expression of Met kinase. Inaddition, they are particularly suitable for use in diagnostic methodsfor diseases in connection with unregulated or disturbed Met Kinaseactivity.

It can be shown that the compounds according to the invention have anantiproliferative action in vivo in a xenotransplant tumour model. Thecompounds according to the invention are administered to a patienthaving a hyperproliferative disease, for example to inhibit tumourgrowth, to reduce inflammation associated with a lymphoproliferativedisease, to inhibit transplant rejection or neurological damage due totissue repair, etc. The present compounds are suitable for prophylacticor therapeutic purposes. As used herein, the term “treatment” is used torefer to both prevention of diseases and treatment of pre-existingconditions. The prevention of proliferation is achieved byadministration of the compounds according to the invention prior to thedevelopment of overt disease, for example to prevent the growth oftumours, prevent metastatic growth, diminish restenosis associated withcardiovascular surgery, etc. Alternatively, the compounds are used forthe treatment of ongoing diseases by stabilising or improving theclinical symptoms of the patient.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro tests.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to induce cell death or to inhibitmigration, usually between about one hour and one week. In vitro testingcan be carried out using cultivated cells from a biopsy sample. Theviable cells remaining after the treatment are then counted.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models (for example Khwaja et al., EMBO, 1997, 16, 2783-93)and models of transgenic animals (for example White et al., Oncogene,2001, 20, 7064-7072). For the determination of certain stages in thesignal transduction cascade, interacting compounds can be utilised inorder to modulate the signal (for example Stephens et al., BiochemicalJ., 2000, 351, 95-105). The compounds according to the invention canalso be used as reagents for testing kinase-dependent signaltransduction pathways in animals and/or cell culture models or in theclinical diseases mentioned in this application.

Measurement of the kinase activity is a technique which is well known tothe person skilled in the art. Generic test systems for thedetermination of the kinase activity using substrates, for examplehistone (for example Alessi et al., FEBS Lett. 1996, 399, 3, pages333-338) or the basic myelin protein, are described in the literature(for example Campos-González, R. and Glenney, Jr., J. R. 1992, J. Biol.Chem. 267, page 14535).

For the identification of kinase inhibitors, various assay systems areavailable. In scintillation proximity assay (Sorg et al., J. of.Biomolecular Screening, 2002, 7, 11-19) and flashplate assay, theradioactive phosphorylation of a protein or peptide as substrate withγATP is measured. In the presence of an inhibitory compound, a decreasedradioactive signal, or none at all, is detectable. Furthermore,homogeneous time-resolved fluorescence resonance energy transfer(HTR-FRET) and fluorescence polarisation (FP) technologies are suitableas assay methods (Sills et al., J. of Biomolecular Screening, 2002,191-214).

Other non-radioactive ELISA assay methods use specificphospho-antibodies (phospho-ABs). The phospho-AB binds only thephosphorylated substrate. This binding can be detected bychemiluminescence using a second peroxidase-conjugated anti-sheepantibody (Ross et al., 2002, Biochem. J.).

There are many diseases associated with deregulation of cellularproliferation and cell death (apoptosis). The conditions of interestinclude, but are not limited to, the following. The compounds accordingto the invention are suitable for the treatment of various conditionswhere there is proliferation and/or migration of smooth muscle cellsand/or inflammatory cells into the intimal layer of a vessel, resultingin restricted blood flow through that vessel, for example in the case ofneointimal occlusive lesions. Occlusive graft vascular diseases ofinterest include atherosclerosis, coronary vascular disease aftergrafting, vein graft stenosis, peri-anastomatic prosthetic restenosis,restenosis after angioplasty or stent placement, and the like.

PRIOR ART

Dihydropyridazinones for combating cancer are described in WO 03/037349A1.

Other pyridazines for the treatment of diseases of the immune system,ischaemic and inflammatory diseases are known from EP 1 043 317 A1 andEP 1 061 077 A1.

EP 0 738 716 A2 and EP 0 711 759 B1 describe other dihydropyridazinonesand pyridazinones as fungicides and insecticides.

Other pyridazinones are described as cardiotonic agents in U.S. Pat. No.4,397,854.

JP 57-95964 discloses other pyridazinones.

Other pyridazinone derivatives are described as Met kinase inhibitors inWO 2008/017361 and WO 2007/065518.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   -   D denotes a five- or six-membered unsaturated or aromatic        heterocycle having 1 to 3 N, O and/or S atoms, which may be        unsubstituted or mono-, di- or trisubstituted by Hal and/or A,    -   R¹ denotes OH, OA, O[C(R⁵)₂]_(n)Ar, O[C(R⁵)₂]_(n)Het,        O[C(R⁵)₂]_(p)N(R⁵)₂, N(R⁵)₂, NR⁵[C(R⁵)₂]_(n)Ar,        NR⁵[C(R⁵)₂]_(n)Het, NR⁵[C(R⁵)₂]_(p)N(R⁵)₂, COOR⁵, CON(R⁵)₂,        CONR⁵[C(R⁵)₂]_(p)N(R⁵)₂, CONR⁵[C(R⁵)₂]_(p)OR⁵,        CONR⁵[C(R⁵)₂]_(n)Het, COHet or COA,    -   R² denotes H, A, Hal, OH, OA, N(R⁵)₂, N═CR⁵N(R⁵)₂, SR⁵, NO₂, CN,        COOR⁵, CON(R⁵)₂, NR⁵COA, NR⁵SO₂A, SO₂N(R⁵)₂, S(O)_(m)A,        [C(R⁵)₂]_(n)N(R⁵)₂, [C(R⁵)₂]_(n)Het, O[C(R⁵)₂]_(p)N(R⁵)₂,        O[C(R⁵)₂]_(n)Het, S[C(R⁵)₂]_(p)N(R⁵)₂, S[C(R⁵)₂]_(n)Het,        NR⁵[C(R⁵)₂]_(p)N(R⁵)₂, —NR⁵[C(R⁵)₂]_(n)Het, NHCON(R⁵)₂,        NHCONH[C(R⁵)₂]_(p)N(R⁵)₂, NHCONH[C(R⁵)₂]_(n)Het,        NHCO[C(R⁵)₂]_(p)N(R⁵)₂, NHCO[C(R⁵)₂]_(n)Het, CON(R⁵)₂,        CONR⁵[C(R⁵)₂]_(p)N(R⁵)₂, CONR⁵[C(R⁵)₂]_(n)Het, COHet, COA,        O[C(R⁵)₂]_(n)NR⁵COZ, O[C(R⁵)₂]_(n)NR²COHet¹,        O[C(R⁵)₂]_(n)Cyc[C(R⁵)₂]_(n)(R⁵)₂,        O[C(R⁵)₂]_(n)Cyc[C(R⁵)₂]_(n)R⁵,        O[C(R⁵)₂]_(n)Cyc[C(R⁵)₂]_(n)Het¹,

-   -    O[C(R⁵)₂]_(n)CR⁵(NR⁵)₂COOR⁵,        O[C(R⁵)₂]_(n)NR⁵CO[C(R⁵)₂]_(n)NR⁵COA, O[C(R⁵)₂]_(n)NR⁵COOA,        O[C(R⁵)₂]_(n)CO—NR⁵-A, O[C(R⁵)₂]_(n)CO—NR⁵—[C(R⁵)₂]_(n)Het¹,        O[C(R⁵)₂]_(n)CONH₂, O[C(R⁵)₂]_(n)CONHA, O[C(R⁵)₂]_(n)CONA₂,        O[C(R⁵)₂]_(n)CO—NR⁵—[C(R²)₂]_(n)N(R⁵)₂ or OCOA,    -   Z denotes CR⁵(NR⁵)₂CR⁵(OR⁵)A,    -   R³ denotes H or A,    -   R⁴ denotes H, A or Hal,    -   R⁵ denotes H or A′,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which 1-7 H atoms may be replaced by OH, F, Cl and/or Br,        -   and/or in which one or two CH₂ groups may be replaced by O,            NH, S, SO, SO₂ and/or CH═CH groups,        -   or        -   cyclic alkyl having 3-7 C atoms, in which 1-7 H atoms may be            replaced by OH, F, Cl and/or Br,    -   A′ denotes unbranched or branched alkyl having 1-6 C atoms, in        which 1-5 H atoms may be replaced by F,    -   Cyc denotes cycloalkylene having 3-7 C atoms,    -   Ar denotes phenyl, naphthyl or biphenyl, each of which is        unsubstituted or mono-, di- or trisubstituted by Hal, A, OR⁵,        N(R⁵)₂, SR⁵, NO₂, CN, COOR⁵, CON(R⁵)₂, NR⁵COA, NR⁵SO₂A,        SO₂N(R⁵)₂, S(O)_(m)A, CO-Het¹, [C(R⁵)₂]_(n)N(R⁵)₂,        [C(R⁵)₂]_(n)Het¹, O[C(R⁵)₂]_(p)N(R⁵)₂, O[C(R⁵)₂]_(n)Het¹,        NHCOOA, NHCON(R⁵)₂, NHCOO[C(R⁵)₂]_(p)N(R⁵)₂,        NHCOO[C(R⁵)₂]_(n)Het¹, NHCONH[C(R⁵)₂]_(p)N(R⁵)₂,        NHCONH[C(R⁵)₂]_(n)Het¹, OCONH[C(R⁵)₂]_(p)N(R⁵)₂ and/or        OCONH[C(R⁵)₂]_(n)Het¹,    -   Het denotes a mono-, bi- or tricyclic saturated, unsaturated or        aromatic heterocycle having 1 to 4 N, O and/or S atoms, which        may be =substituted or mono-, di- or trisubstituted by Hal, A,        OR⁵, N(R⁵)₂, SR⁵, NO₂, CN, COOR⁵, CON(R⁵)₂, NR⁵COA, NR⁵SO₂A,        SO₂N(R⁵)₂, S(O)_(m)A, CO-Het¹, [C(R⁵)₂]_(n)—N(R⁵)₂,        [C(R⁵)₂]_(n)Het¹, O[C(R⁵)₂]_(p)N(R⁵)₂, O[C(R⁵)₂]_(n)Het¹,        NHCOOA, NHCON(R⁵)₂, NHCOO[C(R⁵)₂]_(p)N(R⁵)₂,        NHCOO[C(R⁵)₂]_(n)Het¹, NHCONH[C(R⁵)₂]_(p)N(R⁵)₂,        NHCONH[C(R⁵)₂]_(n)Het¹, OCONH[C(R⁵)₂]_(p)N(R⁵)₂,        OCONH[C(R⁵)₂]_(n)Het¹, CHO, COA, ═S, ═NH, ═NA and/or ═O        (carbonyl oxygen),    -   Het¹ denotes a monocyclic saturated heterocycle having 1 to 2 N        and/or O atoms, which may be mono- or disubstituted by A, OA,        OH, Hal and/or ═O (carbonyl oxygen),    -   Hal denotes F, Cl, Br or I,    -   m denotes 0, 1 or 2,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 2, 3, 4, 5, or 6,    -   q denotes 1, 2, 3, 4 or 5,        and pharmaceutically usable salts, tautomers and stereoisomers        thereof, including mixtures thereof in all ratios,

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds. The term solvates of thecompounds is taken to mean adductions of inert solvent molecules ontothe compounds which form owing to their mutual attractive force.solvates are, for example, mono- or dihydrates or alkoxides.

Pharmaceutically usable derivatives are taken to mean, for example, thesalts of the compounds according to the invention and also so-calledprodrug compounds.

Prodrug derivatives are taken to mean compounds of the formula I whichhave been modified by means of, for example, alkyl or acyl groups,sugars or oligopeptides and Which are rapidly cleaved in the organism toform the effective compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active ingredient which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder.

The term “therapeutically effective amount” also encompasses the amountswhich are effective for increasing normal physiological function.

The invention also relates to the use of mixtures of the compounds ofthe formula I, for example mixtures of two diastereomers, for example inthe ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI according to Claims 1-12 and pharmaceutically usable salts, tautomersand stereoisomers thereof, characterised in that

-   -   a) a compound of the formula II

-   -   -   in which R¹ has the meaning indicated in Claim 1,

    -    is reacted with a compound of the formula III

-   -   -   in which D, R², R³ and R⁴ have the meanings indicated in            Claim 1 and        -   L denotes Cl, Br, I or a free or reactively functionally            modified OH group,

    -    or

    -   b) in that they are liberated from one of their functional        derivatives by treatment with a solvolysing or hydrogenolysing        agent,

and/or a base or acid of the formula is converted into one of its salts.

Above and below, the radicals D, R¹, R², R³ and R⁴ have the meaningsindicated for the formula I, unless expressly stated otherwise.

A denotes alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl, furthermoreethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl,furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl.

Cyclic alkyl(cycloalkyl) preferably denotes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

A furthermore denotes unbranched or branched alkyl having 1-6 C atoms,in which, in addition, one or two CH₂ groups may be replaced by O. Atherefore preferably also denotes 2-hydroxyethyl, 3-hydroxypropyl,2-methoxyethyl or 3-methoxypropyl.

A′ denotes alkyl, this is unbranched (linear) or branched, and has 1, 2,3, 4, 5 or 6 C atoms. A′ preferably denotes methyl, furthermore ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermorealso pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-,2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A′ very particularly preferably denotes methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl ortrifluoromethyl.

R¹ preferably denotes OH, OA, O[C(R⁵)₂]_(n)Ar, N(R⁵)₂, CON(R⁵)₂ orNR⁵[C(R⁵)₂]_(n)Ar.

R² preferably denotes [C(R⁵)₂]_(n)Het or O[C(R⁵)₂]_(n)N(R⁵)₂.

R³ preferably denotes H or Methyl.

R⁴ preferably denotes H.

R⁵ preferably denotes H, methyl, ethyl, propyl or butyl, veryparticularly preferably H or methyl.

n preferably denotes 0, 1 or 2.

p preferably denotes 2 or 3.

q preferably denotes 1, 2, 3 or 4, very particularly preferably 1.

Ar denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-nitrophenyl, o-, m- or p-aminophenyl, o-, m- orp-(N-methylamino)phenyl, o-, m- or p-(N-methylaminocarbonyl)phenyl, o-,m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, m- orp-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m-or p-methylsulfanylphenyl, o-, m- or p-cyanophenyl, o-, m- orp-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- orp-aminosulfonylphenyl, furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl,3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-,2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl,2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl,2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl,

Ar particularly preferably denotes phenyl.

Irrespective of further substitutions, Het denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-,6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-bent-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, further preferably 1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4-, -5-yl or2,1,3-benzoxadiazol-5-yl or dibenzofuranyl.

The heterocyclic radicals may also be partially or fully hydrogenated.Irrespective of further substitutions, Het can thus also denote, forexample, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4-or 5-furyl, tetrahydro-2- or -3-furyl, tetrahydro-2- or -3-thienyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-,-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or-4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-,2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl,3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl,2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl,1,3-dihydroindole, 2-oxo-1,3-dihydroindole or2-oxo-2,3-dihydrobenzimidazolyl.

Het particularly preferably denotes a monocyclic aromatic heterocyclehaving 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-or disubstituted by [C(R⁵)₂]_(n)Het¹.

Het very particularly preferably denotes pyrazolyl, pyridinyl,pyrimidinyl, furyl, thienyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolylor isoxazolyl, where the radicals may also be mono- or disubstituted by[C(R⁵)₂]_(n)Het¹.

Het¹ preferably denotes piperidinyl, pyrrolidinyl, morpholinyl,piperazinyl, oxazolidinyl or imidazolidinyl, where the radicals may alsobe mono- or disubstituted by ═O and/or A.

Het¹ very particularly preferably denotes piperidinyl, pyrrolidinyl,morpholinyl, piperazinyl, oxazolidinyl or imidazolidinyl, where theradicals may also be monosubstituted by A.

D preferably denotes thiazolediyl, thiophenediyl, furandiyl,pyrrolediyl, oxazolediyl, isoxazolediyl, oxadiazolediyl, pyrazolediyl,imidazolediyl, thiadiazolediyl, pyridazinediyl, pyrazinediyl,pyridinediyl or pyrimidinediyl, where the radicals may also be mono-,di- or trisubstituted by Hal and/or A, very particularly preferablythiazolediyl, thiophenediyl, furandiyl, pyrrolediyl, oxazolediyl,isoxazolediyl, oxadiazolediyl, pyrazolediyl, imidazolediyl,thiadiazolediyl, pyridazinediyl, pyrazinediyl, pyridinediyl orpyrimidinediyl.

Hal preferably denotes F, Cl or Br, but also I, particularly preferablyF or Cl.

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to II, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   -   in Ia R¹ denotes OH, OA, O[C(R⁵)₂]_(n)Ar, N(R⁵)₂, CON(R⁵)₂ or        NR⁵[C(R⁵)₂]_(n)Ar;    -   in Ib R² denotes [C(R⁵)₂]_(n)Het or O[C(R⁵)₂]_(p)N(R⁵)₂;    -   in Ic R³ denotes H or methyl;    -   in Id Ar denotes phenyl;    -   in Ie A denotes unbranched or branched alkyl having 1-6 C atoms,        -   in which 1-5 H atoms may be replaced by F, and/or in which            one or two CH₂ groups may be replaced by O;    -   in If R⁴ denotes H;    -   in Ig Het denotes a monocyclic aromatic heterocycle having 1 to        4 N, O and/or S atoms, which may be unsubstituted or mono- or        disubstituted by [C(R⁵)₂]_(n)Het¹;    -   in Ih Het denotes pyrazolyl, pyridinyl, pyrimidinyl, furyl,        thienyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl or        isoxazolyl, where the radicals may also be mono- or        disubstituted by [C(R⁵)₂]_(n)Het¹;    -   in Ii Het¹ denotes piperidinyl, pyrrolidinyl, morpholinyl,        piperazinyl, oxazolidinyl or imidazolidinyl, where the radicals        may also be mono- or disubstituted by ═O and/or A;    -   in Ij D denote thiazolediyl, thiophenediyl, furandiyl,        pyrrolediyl, oxazolediyl, isoxazolediyl, oxadiazolediyl,        pyrazolediyl, imidazolediyl, thiadiazolediyl, pyridazinediyl,        pyrazinediyl, pyridinediyl or pyrimidinediyl,        -   where the radicals may also be mono-, di- or trisubstituted            by Hal and/or A;    -   in Ik R¹ denotes OH, OA, O[C(R⁵)₂]_(n)Ar, N(R⁵)₂, CON(R⁵)₂ or        NR⁵[C(R⁵)₂]_(n)Ar,    -   R² denotes [C(R⁵)₂]_(n)Het or O[C(R⁵)₂]_(p)N(R⁵)₂,    -   R³ denotes H or methyl,    -   R⁴ denotes H,    -   R⁵ denotes H or A′,    -   A denotes unbranched or branched alkyl having 1-6 C atoms,        -   in which 1-5 H atoms may be replaced by F,        -   and/or in which one or two CH₂ groups may be replaced by O,    -   A′ denotes unbranched or branched alkyl having 1-6 C atoms, in        which 1-5 H atoms may be replaced by F,    -   Ar denotes phenyl,    -   Het denotes a monocyclic aromatic heterocycle having 1 to 4 N, O        and/or S atoms, which may be unsubstituted or mono- or        disubstituted by [C(R⁵)₂]_(n)Het¹,    -   Het¹ denotes piperidinyl, pyrrolidinyl, morpholinyl,        piperazinyl, oxazolidinyl or imidazolidinyl, where the radicals        may also be mono- or disubstituted by ═O and/or A,    -   D denotes thiazolediyl, thiophenediyl, furandiyl, pyrrolediyl,        oxazolediyl, isoxazolediyl, oxadiazolediyl, pyrazolediyl,        imidazolediyl, thiadiazolediyl, pyridazinediyl, pyrazinediyl,        pyridinediyl or pyrimidinediyl,        -   where the radicals may also be mono-, di- or trisubstituted            by Hal and/or A,    -   Hal denotes F, Cl, Br or I,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 2, 3, 4, 5, or 6;    -   in II R¹ denotes OH, OA, O[C(R⁵)₂]_(n)Ar, N(R⁵)₂, CON(R⁵)₂ or        NR⁵[C(R⁵)₂]_(n)Ar,    -   R² denotes [C(R⁵)₂]_(n)Het or O[C(R⁵)₂]_(p)N(R⁵)₂,    -   R³ denotes H or methyl,    -   R⁴ denotes H,    -   R⁵ denotes H or A′,    -   A denotes unbranched or branched alkyl having 1-6 C atoms,        -   in which 1-5 H atoms may be replaced by F,        -   and/or in which one or two CH₂ groups may be replaced by O,    -   A′ denotes unbranched or branched alkyl having 1-6 C atoms,    -   Ar denotes phenyl,    -   Het denotes pyrazolyl, pyridinyl, pyrimidinyl, furyl, thienyl,        oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl or isoxazolyl, where        the radicals may also be mono- or disubstituted by        [C(R⁵)₂]_(n)Het¹,    -   Het¹ denotes piperidinyl, pyrrolidinyl, morpholinyl,        piperazinyl, oxazolidinyl or imidazolidinyl, where the radicals        may also be monosubstituted by A,    -   D denotes thiazolediyl, thiophenediyl, furandiyl, pyrrolediyl,        oxazolediyl, isoxazolediyl, oxadiazolediyl, pyrazolediyl,        imidazolediyl, thiadiazolediyl, pyridazinediyl, pyrazinediyl,        pyridinediyl or pyrimidinediyl,    -   Hal denotes F, Cl, Br or I,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 2, 3 or 4;

and pharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se which are notmentioned here in greater detail.

Compounds of the formula I can preferably be obtained by reacting acompound of the formula II with, a compound of the formula III.

In the compounds of the formula III, L preferably denotes OH, Cl, Br, Ior a free or reactively modified OH group, such as, for example, anactivated ester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms(preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) orarylsulfonyloxy having 6-10 C atoms (preferably phenyl- orp-tolylsulfonyloxy).

The reaction is generally carried out in the presence of an acid-bindingagent, preferably an organic base, such as DIPEA, triethylamine,dimethylaniline, pyridine or quinoline.

The addition of an alkali or alkaline earth metal hydroxide, carbonateor bicarbonate or another salt of a weak acid of the alkali or alkalineearth metals, preferably of potassium, sodium, calcium or caesium, mayalso be favourable.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between 0° and 100°, in particular between about 60° andabout 90°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon, tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tent-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particular preference is given to ethanol, toluene, dimethoxyethane orTHF.

Particular preference is given to the reaction with triphenylphosphineand an azodicarboxylate if L denotes OH in the compounds of the formulaIII. In this case, the reaction is preferably carried out in THF attemperatures between −15 and 5°.

Compounds of the formula I can furthermore preferably be obtained byconverting a radical R¹ and/or R² into another radical R¹ and/or R²

by

i) replacing a halogen or hydroxyl group by an alkyl radical, aheterocyclic radical or an aryl radical,

ii) converting a carboxyl group into an amide,

iii) alkylating an amine,

iv) etherifying a hydroxyl group.

The exchange of a halogen atom is preferably carried out under theconditions of a Suzuki coupling.

Furthermore, free amino groups can be acylated in a conventional mannerusing an acid chloride or anhydride or alkylated using an unsubstitutedor substituted alkyl halide, advantageously in an inert solvent, such asdichloromethane or THF, and/or in the presence of a base, such astriethylamine or pyridine, at temperatures between −60 and +30°.

The compounds of the formulae I can furthermore be obtained byliberating them from their functional derivatives by solvolysis, inparticular hydrolysis, or by hydrogenolysis.

Preferred starting materials for the solvolysis or hydrogenolysis arethose which contain corresponding protected amino and/or hydroxyl groupsinstead of one or more free amino and/or hydroxyl groups, preferablythose which carry an amino-protecting group instead of an H atom bondedto an N atom, for example those which conform to the formula I, butcontain an NHR′ group (in which R′ is an amino-protecting group, forexample BOC or CBZ) instead of an NH₂ group.

Preference is furthermore given to starting materials which carry ahydroxyl-protecting group instead of the H atom of a hydroxyl group, forexample those which conform to the formula I, but contain an R″O-phenylgroup (in which R″ is a hydroxyl-protecting group) instead of ahydroxyphenyl group.

It is also possible for a plurality of—identical or different—protectedamino and/or hydroxyl groups to be present in the molecule of thestarting material. If the protecting groups present are different fromone another, they can in many cases be cleaved off selectively.

The term “amino-protecting group” is known in general terms and relatesto groups which are suitable for protecting (blocking) an amino groupagainst chemical reactions, but are easy to remove after the desiredchemical reaction has been carried out elsewhere in the molecule.Typical of such groups are, in particular, unsubstituted or substitutedacyl, aralkoxymethyl or aralkyl groups. Since the amino-protectinggroups are removed after the desired reaction (or reaction sequence),their type and size are furthermore not crucial; however, preference isgiven to those having 1-20, in particular 1-8, carbon atoms. The term“acyl group” is to be understood in the broadest sense in connectionwith the present process. It includes acyl groups derived fromaliphatic, araliphatic, aromatic or heterocyclic carboxylic acids orsulfonic acids, and, in particular, alkoxycarbonyl, aryloxycarbonyl andespecially aralkoxycarbonyl groups. Examples of such acyl groups arealkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such asphenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such asPOA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, BOC and 2-iodoethoxycarbonyl;aralkoxycarbonyl, such as CBZ (“carbobenzoxy”),4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr, Pbfand Pmc. Preferred amino-protecting groups are BOC and Mtr, furthermoreCBZ, Fmoc, benzyl and acetyl.

The term “hydroxyl-protecting group” is likewise known in general termsand relates to groups which are suitable for protecting a hydroxyl groupagainst chemical reactions, but are easy to remove after the desiredchemical reaction has been carried out elsewhere in the molecule.Typical of such groups are the above-mentioned unsubstituted orsubstituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.The nature and size of the hydroxyl-protecting groups are not crucialsince they are removed again after the desired chemical reaction orreaction sequence; preference is given to groups having 1-20, inparticular 1-10, carbon atoms. Examples of hydroxyl-protecting groupsare, inter alia, tert-butoxycarbonyl, benzyl, p-nitrobenzoyl,p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butylare particularly preferred. The COON groups in aspartic acid andglutamic acid are preferably protected in the form of their tert-butylesters (for example Asp(OBut)).

The compounds of the formula I are liberated from their functionalderivatives—depending on the protecting group used—for example usingstrong acids, advantageously using TFA or perchloric acid, but alsousing other strong inorganic acids, such as hydrochloric acid orsulfuric acid, strong organic carboxylic acids, such as trichloroaceticacid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. Thepresence of an additional inert solvent is possible, but is not alwaysnecessary. Suitable inert solvents are preferably organic, for examplecarboxylic acids, such as acetic acid, ethers, such as tetrahydrofuranor dioxane, amides, such as DMF, halogenated hydrocarbons, such asdichloromethane, furthermore also alcohols, such as methanol, ethanol orisopropanol, and water. Mixtures of the above-mentioned solvents arefurthermore suitable. TFA is preferably used in excess without additionof a further solvent, and perchloric acid is preferably used in the formof a mixture of acetic acid and 70% perchloric acid in the ratio 9:1.The reaction temperatures for the cleavage are advantageously betweenabout 0 and about 50°, preferably between 15 and 30° (room temperature).

The BOC, OBut, Pbf, Pmc and Mtr groups can, for example, preferably becleaved off using TFA in dichloromethane or using approximately 3 to 5NHCl in dioxane at 15-30°, and the FMOC group can be cleaved off using anapproximately 5 to 50% solution of dimethylamine, diethylamine orpiperidine in DMF at 15-30°.

The trityl group is employed to protect the amino acids histidine,asparagine, glutamine and cysteine. They are cleaved off, depending onthe desired end product, using TFA/10% thiophenol, with the trityl groupbeing cleaved off from all the said amino acids; on use of TFA/anisoleor TFA/thioanisole, only the trityl group of His, Asn and Gln is cleavedoff, whereas it remains on the Cys side chain.

The Pbf (pentamethylbenzofuranyl) group is employed to protect Arg. Itis cleaved off using, for example, TFA in dichloromethane.

Hydrogenolytically removable protecting groups (for example CBZ orbenzyl) can be cleaved off, for example, by treatment with hydrogen inthe presence of a catalyst (for example a noble-metal catalyst, such aspalladium, advantageously on a support, such as carbon). Suitablesolvents here are those indicated above, in particular, for example,alcohols, such as methanol or ethanol, or amides, such as DMF. Thehydrogenolysis is generally carried out at temperatures between about 0and 100° and pressures between about 1 and 200 bar, preferably at 20-30°and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, forexample, on 5 to 10% Pd/C in methanol or using ammonium formate (insteadof hydrogen) on Pd/C in methanol/DMF at 20-30°.

Pharmaceutical Salts and other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formulaare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate,benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate,camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate,citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine(benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine andtris(hydroxymethyl)methylamine(tromethamine), but this is not intendedto represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

Particular preference is given to hydrochloride, dihydrochloride,hydrobromide; maleate, mesylate, phosphate, sulfate and succinate.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken toMean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable salts andstereoisomers thereof, including mixtures thereof in all ratios, andoptionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets: A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example; syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tabletting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt; talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps: A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula I and salts thereof can also beadministered in the form of liposome delivery systems, such as, forexample, small unilamellar vesicles, large unilamellar vesicles andmultilamellar vesicles. Liposomes can be formed from variousphospholipids, such as, for example, cholesterol, stearylamine orphosphatidylcholines.

The compounds of the formula I and the salts thereof can also bedelivered using monoclonal antibodies as individual carriers to whichthe compound molecules are coupled. The compounds can also be coupled tosoluble polymers as targeted medicament carriers. Such polymers mayencompass polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials; and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula Idepends on a number of factors, including, for example, the age andweight of the animal, the precise condition that requires treatment, andits severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound according to theinvention for the treatment of neoplastic growth, for example colon orbreast carcinoma, is generally in the range from 0.1 to 100 mg/kg ofbody weight of the recipient (mammal) per day and particularly typicallyin the range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as a single dose perday or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or solvate or of a physiologicallyfunctional derivative thereof can be determined as the fraction of theeffective amount of the compound according to the invention per se. Itcan be assumed that similar doses are suitable for the treatment ofother conditions mentioned above.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable salts andstereoisomers thereof, including mixtures thereof in all ratios, and atleast one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   -   (a) an effective amount of a compound of the formula I and/or        pharmaceutically usable salts and stereoisomers thereof,        including mixtures thereof in all ratios,        -   and    -   (b) an effective amount of a further medicament active        ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula I and/or pharmaceutically usable salts and stereoisomersthereof, including mixtures thereof in all ratios,

and an effective amount of a further medicament active ingredient indissolved or lyophilised form.

Use

The present compounds are suitable as pharmaceutical active ingredientsfor mammals, especially for humans, in the treatment of tyrosinekinase-induced diseases. These diseases include the proliferation oftumour cells, pathological neovascularisation (or angiogenesis) whichpromotes the growth of solid tumours, ocular neovascularisation(diabetic retinopathy, age-induced macular degeneration and the like)and inflammation (psoriasis, rheumatoid arthritis and the like).

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention of cancer.Preferred carcinomas for the treatment originate from the group cerebralcarcinoma, urogenital tract carcinoma, carcinoma of the lymphaticsystem, stomach carcinoma, laryngeal carcinoma and lung carcinoma. Afurther group of preferred forms of cancer are monocytic leukaemia, lungadenocarcinoma, small-cell lung carcinomas, pancreatic cancer,glioblastomas and breast carcinoma.

Also encompassed is the use of the compounds according to Claim 1according to the invention and/or physiologically acceptable saltsthereof for the preparation of a medicament for the treatment orprevention of a disease in which angiogenesis is implicated.

Such a disease in which angiogenesis is implicated is an ocular disease,such as retinal vascularisation, diabetic retinopathy, age-inducedmacular degeneration and the like.

The use of compounds of the formula I and/or physiologically acceptablesalts and solvates thereof for the preparation of a medicament for thetreatment or prevention of inflammatory diseases also falls within thescope of the present invention. Examples of such inflammatory diseasesinclude rheumatoid arthritis, psoriasis, contact dermatitis, delayedhypersensitivity reaction and the like.

Also encompassed is the use of the compounds of the formula I and/orphysiologically acceptable salts thereof for the preparation of amedicament for the treatment or prevention of a tyrosine kinase-induceddisease or a tyrosine kinase-induced condition in a mammal, in which tothis method a therapeutically effective amount of a compound accordingto the invention is administered to a sick mammal in need of suchtreatment. The therapeutic amount varies according to the specificdisease and can be determined by the person skilled in the art withoutundue effort.

The present invention also encompasses the use compounds of the formulaI and/or physiologically acceptable salts and solvates thereof for thepreparation of a medicament for the treatment or prevention of retinalvascularisation.

Methods for the treatment or prevention of ocular diseases, such asdiabetic retinopathy and age-induced macular degeneration, are likewisepart of the invention. The use for the treatment or prevention ofinflammatory diseases, such as rheumatoid arthritis, psoriasis, contactdermatitis and delayed hypersensitivity reaction, as well as thetreatment or prevention of bone pathologies from the group osteosarcoma,osteoarthritis and rickets, likewise falls within the scope of thepresent invention.

The expression “tyrosine kinase-induced diseases or conditions” refersto pathological conditions that depend on the activity of one or moretyrosine kinases. Tyrosine kinases either directly or indirectlyparticipate in the signal transduction pathways of a variety of cellularactivities, including proliferation, adhesion and migration anddifferentiation. Diseases associated with tyrosine kinase activityinclude proliferation of tumour cells, pathological neovascularisationthat promotes the growth of solid tumours, ocular neovascularisation(diabetic retinopathy, age-induced macular degeneration and the like)and inflammation (psoriasis, rheumatoid arthritis and the like).

The compounds of the formula I can be administered to patients for thetreatment of cancer, in particular fast-growing tumours.

The invention thus relates to the use of compounds of the formula I, andpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios, for the preparation of a medicament forthe treatment of diseases in which the inhibition, regulation and/ormodulation of kinase signal transduction plays a role.

Preference is given here to Met kinase.

Preference is given to the use of compounds of the formula I, andpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios,

for the preparation of a medicament for the treatment of diseases whichare influenced by inhibition of tyrosine kinases by the compoundsaccording to Claim 1.

Particular preference is given to the use for the preparation of amedicament for the treatment of diseases which are influenced byinhibition of Met kinase by the compounds according to Claim 1.

Especial preference is given to the use for the treatment of a diseasewhere the disease is a solid tumour.

The solid tumour is preferably selected from the group of tumours of thelung, squamous epithelium, the bladder, the stomach, the kidneys, ofhead and neck, the oesophagus, the cervix, the thyroid, the intestine,the liver, the brain, the prostate, the urogenital tract, the lymphaticsystem, the stomach and/or the larynx.

The solid tumour is furthermore preferably selected from the group lungadenocarcinoma, small-cell lung carcinomas, pancreatic cancer,glioblastomas, colon carcinoma and breast carcinoma.

Preference is furthermore given to the use for the treatment of a tumourof the blood and immune system, preferably for the treatment of a tumourselected from the group of acute myeloid leukaemia, chronic myeloidleukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined herein may be applied as a soletherapy or may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy. Such chemotherapymay include one or more of the following categories of anti-tumouragents:

(i) antiproliferative/antineoplastic/DNA-damaging agents andcombinations thereof, as used in medical oncology, such as alkylatingagents (for example cis-platin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chloroambucil, busulphan and nitrosoureas);antimetabolites (for example antifolates such as fluoropyrimidines like5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosinearabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (forexample anthracyclines, like adriamycin, Neomycin, doxorubicin,daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin andmithramycin); antimitotic agents (for example vinca alkaloids, likevincristine, vinblastine, vindesine and vinorelbine, and taxoids, liketaxol and taxotere); topoisomerase inhibitors (for exampleepipodophyllotoxins, like etoposide and teniposide, amsacrine,topotecan, irinotecan and camptothecin) and cell-differentiating agents(for example all-trans-retinoic acid, 13-cis-retinoic acid andfenretinide);

(ii) cytostatic agents, such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptordownregulators (for example fulvestrant), antiandrogens (for examplebicalutamide, flutamide, nilutamide and cyproterone acetate), LHRHantagonists or LHRH agonists (for example goserelin, leuprorelin andbuserelin), progesterones (for example megestrol acetate), aromataseinhibitors (for example as anastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase, such as finasteride;

(iii) agents which inhibit cancer cell invasion (for examplemetalloproteinase inhibitors, like marimastat, and inhibitors ofurokinase plasminogen activator receptor function);

(iv) inhibitors of growth factor function, for example such inhibitorsinclude growth factor antibodies, growth factor receptor antibodies (forexample the anti-erbb2 antibody trastuzumab [Herceptin™] and theanti-erbb1 antibody cetuximab [C225]), farnesyl transferase inhibitors,tyrosine kinase inhibitors and serine/threonine kinase inhibitors, forexample inhibitors of the epidermal growth factor family (for exampleEGFR family tyrosine kinase inhibitors, such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)), for example inhibitors of the platelet-derived growth factorfamily and for example inhibitors of the hepatocyte growth factorfamily;

(v) antiangiogenic agents, such as those which inhibit the effects ofvascular endothelial growth factor, (for example the anti-vascularendothelial cell growth factor antibody bevacizumab [Avastin™],compounds such as those disclosed in published international patentapplications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) andcompounds that work by other mechanisms (for example linomide,inhibitors of integrin αvβ3 function and angiostatin);

(vi) vessel-damaging agents, such as combretastatin A4 and compoundsdisclosed in international patent applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-Ras antisense;

(viii) gene therapy approaches, including, for example, approaches forreplacement of aberrant genes, such as aberrant p53 or aberrant BRCA1 orBRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches, such asthose using cytosine deaminase, thymidine kinase or a bacterialnitroreductase enzyme, and approaches for increasing patient toleranceto chemotherapy or radiotherapy, such as multi-drug resistance genetherapy; and

(ix) immunotherapy approaches, including, for example, ex-vivo andin-vivo approaches for increasing the immunogenicity of patient tumourcells, such as transfection with cytokines, such as interleukin 2,interleukin 4 or granulocyte-macrophage colony stimulating factor,approaches for decreasing T-cell anergy, approaches using transfectedimmune cells, such as cytokine-transfected dendritic cells, approachesusing cytokine-transfected tumour cell lines, and approaches usinganti-idiotypic antibodies.

The medicaments from Table 1 below are preferably, but not exclusively,combined with the compounds of the formula I.

TABLE 1 Alkylating agents Cyclophosphamide Lomustine BusulfanProcarbazine Ifosfamide Altretamine Melphalan Estramustine phosphateHexamethylmelamine Mechloroethamine Thiotepa Streptozocin ChloroambucilTemozolomide Dacarbazine nustine Carmustine Platinum agents CisplatinCarboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin(Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson TetraplatinMatthey) BBR-3464 Ormiplatin (Hoffmann-La Roche) Iproplatin SM-11355(Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine TomudexGemcitabine Trimetrexate Capecitabine Deoxycoformycin 5-FluorouracilFludarabine Floxuridine Pentostatin 2-Chlorodesoxyadenosine Raltitrexed6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen)Cytarabine Clofarabine (Bioenvision) 2-Fluorodesoxycytidine Irofulven(MGI Pharma) Methotrexate DMDC (Hoffmann-La Idatrexate Roche)Ethynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan (SuperGen)inhibitors Epirubicin Exatecan mesylate (Daiichi) Etoposide Quinamed(ChemGenex) Teniposide or mitoxantrone Gimatecan (Sigma- Tau) Irinotecan(CPT-11) Diflomotecan (Beaufour- 7-Ethyl-10- Ipsen) hydroxycamptothecinTAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum) Dexrazoxanet(TopoTarget) J-107088 (Merck & Co) Pixantrone (Novuspharma) BNP-1350(BioNumerik) Rebeccamycin analogue CKD-602 (Chong Kun Dang) (Exelixis)KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharma) Antitumour Dactinomycin(Actinomycin D) Amonafide antibiotics Doxorubicin (Adriamycin) AzonafideDeoxyrubicin Anthrapyrazole Valrubicin Oxantrazole Daunorubicin(Daunomycin) Losoxantrone Epirubicin Bleomycin sulfate (Blenoxan)Therarubicin Bleomycinic acid Idarubicin Bleomycin A Rubidazon BleomycinB Plicamycinp Mitomycin C Porfiromycin MEN-10755 (Menarini)Cyanomorpholinodoxorubicin GPX-100 (Gem Mitoxantron (Novantron)Pharmaceuticals) Antimitotic agents Paclitaxel SB 408075(GlaxoSmithKline) Docetaxel E7010 (Abbott) Colchicine PG-TXL (CellTherapeutics) Vinblastine IDN 5109 (Bayer) Vincristine A 105972 (Abbott)Vinorelbine A 204197 (Abbott) Vindesine LU 223651 (BASF) Dolastatin 10(NCI) D 24851 (ASTA Medica) Rhizoxin (Fujisawa) ER-86526 (Eisai)Mivobulin (Warner-Lambert) Combretastatin A4 (BMS) Cemadotin (BASF)Isohomohalichondrin-B RPR 109881A (Aventis) (PharmaMar) TXD 258(Aventis) ZD 6126 (AstraZeneca) Epothilone B (Novartis) PEG-Paclitaxel(Enzon) T 900607 (Tularik) AZ10992 (Asahi) T 138067 (Tularik) DN-5109(Indena) Cryptophycin 52 (Eli Lilly) AVLB (Prescient Vinflunine (Fabre)NeuroPharma) Auristatin PE (Teikoku Azaepothilon B (BMS) Hormone) BNP-7787 (BioNumerik) BMS 247550 (BMS) CA-4-prodrug (OXiGENE) BMS 184476(BMS) Dolastatin-10 (NrH) BMS 188797 (BMS) CA-4 (OXiGENE) Taxoprexin(Protarga) Aromatase Aminoglutethimide Exemestan inhibitors LetrozoleAtamestan (BioMedicines) Anastrazole YM-511 (Yamanouchi) FormestanThymidylate synthase Pemetrexed (Eli Lilly) Nolatrexed (Eximias)inhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys) DNA antagonistsTrabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide (BaxterInternational) International) Apaziquone (Spectrum Albumin + 32P(Isotope Pharmaceuticals) Solutions) O6-benzylguanine (Paligent)Thymectacin (NewBiotics) Edotreotid (Novartis) Farnesyl transferaseArglabin (NuOncology Labs) Tipifarnib (Johnson & inhibitors Ionafarnib(Schering-Plough) Johnson) BAY-43-9006 (Bayer) Perillyl alcohol (DORBioPharma) Pump inhibitors CBT-1 (CBA Pharma) Zosuquidartrihydrochloride Tariquidar (Xenova) (Eli Lilly) MS-209 (Schering AG)Biricodar dicitrate (Vertex) Histone acetyl Tacedinaline (Pfizer)Pivaloyloxymethyl butyrate transferase inhibitors SAHA (Aton Pharma)(Titan) MS-275 (Schering AG) Depsipeptide (Fujisawa) MetalloproteinaseNeovastat (Aeterna CMT -3 (CollaGenex) inhibitors Laboratories)BMS-275291 (Celltech) Ribonucleoside Marimastat (British Biotech)Tezacitabine (Aventis) reductase Gallium maltolate (Titan) Didox(Molecules for Health) inhibitors Triapin (Vion) TNF-alpha Virulizin(Lorus Therapeutics) Revimid (Celgene) agonists/ CDC-394 (Celgene)antagonists Endothelin-A Atrasentan (Abbot) YM-598 (Yamanouchi) receptorantagonists ZD-4054 (AstraZeneca) Retinoic acid Fenretinide (Johnson &Alitretinoin (Ligand) receptor agonists Johnson) LGD-1550 (ligand)Immunomodulators Interferon Dexosome therapy (Anosys) Oncophage(Antigenics) Pentrix (Australian Cancer GMK (Progenics) Technology)Adenocarcinoma vaccine JSF-154 (Tragen) (Biomira) Cancer vaccine(Intercell) CTP-37 (AVI BioPharma) Norelin (Biostar) JRX-2 (Immuno-Rx)BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics) Synchrovaxvaccines (CTL 3-Alethin (Dovetail) Immuno) CLL-Thera (Vasogen) Melanomavaccine (CTL Immuno) p21-RAS vaccine (GemVax) Hormonal and OestrogensPrednisone antihormonal Conjugated oestrogens Methylprednisolone agentsEthynyloestradiol Prednisolone Chlorotrianisene AminoglutethimideIdenestrol Leuprolide Hydroxyprogesterone caproate GoserelinMedroxyprogesterone Leuporelin Testosterone Bicalutamide Testosteronepropionate Flutamide Fluoxymesterone Octreotide MethyltestosteroneNilutamide Diethylstilbestrol Mitotan Megestrol P-04 (Novogen) Tamoxifen2-Methoxyoestradiol Toremofin (EntreMed) Dexamethasone Arzoxifen (EliLilly) Photodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbidagents Theralux (Theratechnologies) (Yeda) Motexafin-GadoliniumLutetium-Texaphyrin (Pharmacyclics) (Pharmacyclics) Hypericin Tyrosinekinase Imatinib (Novartis) Kahalide F (PharmaMar) inhibitorsLeflunomide(Sugen/ CEP- 701 (Cephalon) Pharmacia) CEP-751 (Cephalon)ZDI839 (AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene Science)PKC412 (Novartis) Canertjnib (Pfizer) Phenoxodiol O Squalamine (Genaera)Trastuzumab (Genentech) SU5416 (Pharmacia) C225 (ImClone) SU6668(Pharmacia) rhu-Mab (Genentech) ZD4190 (AstraZeneca) MDX-H210 (Medarex)ZD6474 (AstraZeneca) 2C4 (Genentech) Vatalanib (Novartis) MDX-447(Medarex) PKI166 (Novartis) ABX-EGF (Abgenix) GW2016 (GlaxoSmithKline)IMC-1C11 (ImClone) EKB-509 (Wyeth) EKB-569 (Wyeth) Various agentsSR-27897 (CCK-A inhibitor, BCX-1777 (PNP inhibitor, Sanofi-Synthelabo)BioCryst) Tocladesine (cyclic AMP Ranpirnase (ribonuclease agonist,Ribapharm) stimulant, Alfacell) Alvocidib (CDK inhibitor, Galarubicin(RNA synthesis Aventis) inhibitor, Dong-A) CV-247 (COX-2 inhibitor, IvyTirapazamine Medical) (reducing agent, SRI P54 (COX-2 inhibitor,International) Phytopharm) N-Acetylcysteine (reducing CapCell ™ (CYP450stimulant, agent, Zambon) Bavarian Nordic) R-Flurbiprofen (NF-kappaBGCS-IOO (gal3 antagonist, inhibitor, Encore) GlycoGenesys) 3CPA(NF-kappaB inhibitor, G17DT immunogen (gastrin Active Biotech)inhibitor, Aphton) Seocalcitol (vitamin D Efaproxiral (oxygenator,receptor agonist, Leo) Allos Therapeutics) 131-I-TM-601 (DNA PI-88(heparanase inhibitor, antagonist, TransMolecular) Progen) Eflornithin(ODC inhibitor, Tesmilifen (histamine ILEX Oncology) antagonist, YMBioSciences) Minodronic acid (osteoclast Histamine (histamine H2inhibitor, Yamanouchi) receptor agonist, Maxim) Indisulam (p53stimulant, Tiazofurin (IMPDH inhibitor, Eisai) Ribapharm) Aplidin (PPTinhibitor, Cilengitide (integrin antagonist, PharmaMar) Merck KGaA)Rituximab (CD20 antibody, SR-31747 (IL-1 antagonist, Genentech)Sanofi-Synthelabo) Gemtuzumab (CD33 CCI-779 (mTOR kinase antibody, WyethAyerst) inhibitor, Wyeth) PG2 (haematopoiesis Exisulind (PDE-Vinhibitor, promoter, Pharmagenesis) Cell Pathways) Immunol ™ (triclosanCP-461 (PDE-V inhibitor, Cell mouthwash, Endo) Pathways)Triacetyluridine (uridine prodrug, AG-2037 (GART inhibitor, Wellstat)Pfizer) SN-4071 (sarcoma agent, WX-UK1 Signature BioScience)(plasminogen activator TransMID-107 ™ inhibitor, Wilex) (immunotoxin, KSBiomedix) PBI-1402 (PMN stimulant, PCK-3145 (apoptosis ProMeticLifeSciences) promoter, Procyon) Bortezomib (proteasome Doranidazole(apoptosis inhibitor, Millennium) promoter, Pola) SRL-172 (T-cellstimulant, CHS-828 (cytotoxic agent, SR Pharma) Leo) TLK-286(glutathione-S Trans-retinic acid transferase inhibitor, Telik)(differentiator, NIH) PT-100 (growth factor agonist, MX6 (apoptosispromoter, Point Therapeutics) MAXIA) Midostaurin (PKC inhibitor, Apomine(apoptosis promoter, Novartis) ILEX Oncology) Bryostatin-1 (PKCstimulant, Urocidin (apoptosis promoter, GPC Biotech) Bioniche) CDA-II(apoptosis promoter, Ro-31-7453 (apoptosis Everlife) promoter, La Roche)SDX-101 (apoptosis promoter, Brostallicin (apoptosis Salmedix) promoter,Pharmacia) Ceflatonin (apoptosis promoter, ChemGenex) Alkylating agentsCyclophosphamide Lomustin Busulfan Procarbazin Ifosfamide AltretaminMelphalan Estramustine phosphate Hexamethylmelamine MechloroethaminThiotepa Streptozocin Chloroambucil Temozolomid Dacarbazine SemustinCarmustine Platinum agents Cisplatin Carboplatin Oxaliplatin ZD-0473(AnorMED) Spiroplatin Lobaplatin (Aetema) CarboxyphthalatoplatinumSatraplatin (Johnson Matthey) Tetraplatin BBR-3464 (Hoffmann-LaOrmiplatin Roche) Iproplatin SM-11355 (Sumitomo) AP-5280 (Access)Antimetabolites Azacytidine Tomudex Gemcitabine TrimetrexateCapecitabine Deoxycoformycin 5-Fluorouracil Fludarabine FloxuridinePentostatin 2-Chlorodesoxyadenosine Raltitrexed 6-MercaptopurineHydroxyurea 6-Thioguanine Decitabine (SuperGen) Cytarabine Clofarabine(Bioenvision) 2-Fluorodesoxycytidine Irofulven (MGI Pharma) MethotrexateDMDC (Hoffmann-La Roche) Idatrexate Ethynylcytidine (Taiho)Topoisomerase Amsacrine Rubitecan (SuperGen) inhibitors EpirubicinExatecan mesylate (Daiichi) Etoposide Quinamed (ChemGenex) Teniposide ormitoxantrone Gimatecan (Sigma- Tau) Irinotecan (CPT-11) Diflomotecan(Beaufour- 7-Ethyl-10- Ipsen) hydroxycamptothecin TAS-103 (Taiho)Topotecan Elsamitrucin (Spectrum) Dexrazoxanet (TopoTarget) J-107088(Merck & Co) Pixantrone (Novuspharma) BNP-1350 (BioNumerik) Rebeccamycinanalogue CKD-602 (Chong Kun Dang) (Exelixis) KW-2170 (Kyowa Hakko)BBR-3576 (Novuspharma) Antitumour Dactinomycin (Actinomycin D) Amonafideantibiotics Doxorubicin (Adriamycin) Azonafide DeoxyrubicinAnthrapyrazole Valrubicin Oxantrazole Daunorubicin (Daunomycin)Losoxantrone Epirubicin Bleomycin sulfate (Blenoxan) TherarubicinBleomycinic acid Idarubicin Bleomycin A Rubidazon Bleomycin BPlicamycinp Mitomycin C Porfiromycin MEN-10755 (Menarini)Cyanomorpholinodoxorubicin GPX-100 (Gem Mitoxantron (Novantron)Pharmaceuticals) Antimitotic agents Paclitaxel SB 408075(GlaxoSmithKline) Docetaxel E7010 (Abbott) Colchicine PG-TXL (CellTherapeutics) Vinblastine IDN 5109 (Bayer) Vincristine A 105972 (Abbott)Vinorelbine A 204197 (Abbott) Vindesine LU 223651 (BASF) Dolastatin 10(NCI) D 24851 (ASTA Medica) Rhizoxin (Fujisawa) ER-86526 (Eisai)Mivobulin (Warner-Lambert) Combretastatin A4 (BMS) Cemadotin (BASF)Isohomohalichondrin-B RPR 109881A (Aventis) (PharmaMar) TXD 258(Aventis) ZD 6126 (AstraZeneca) Epothilone B (Novartis) PEG-Paclitaxel(Enzon) T 900607 (Tularik) AZ10992 (Asahi) T 138067 (Tularik) DN-5109(Indena) Cryptophycin 52 (Eli Lilly) AVLB (Prescient Vinflunine (Fabre)NeuroPharma) Auristatin PE (Teikoku Azaepothilon B (BMS) Hormone) BNP-7787 (BioNumerik) BMS 247550 (BMS) CA-4-prodrug (OXiGENE) BMS 184476(BMS) Dolastatin-10 (NrH) BMS 188797 (BMS) CA-4 (OXiGENE) Taxoprexin(Protarga) Aromatase Aminoglutethimide Exemestan inhibitors LetrozoleAtamestan (BioMedicines) Anastrazole YM-511 (Yamanouchi) FormestanThymidylate synthase Pemetrexed (Eli Lilly) Nolatrexed (Eximias)inhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys) DNA antagonistsTrabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide (BaxterInternational) International) Apaziquone (Spectrum Albumin + 32P(Isotope Pharmaceuticals) Solutions) O6-benzylguanine (PaligentThymectacin (NewBiotics) Edotreotid (Novartis) Farnesyl transferaseArglabin (NuOncology Labs) Tipifarnib (Johnson & inhibitors Ionafarnib(Schering-Plough) Johnson) BAY-43-9006 (Bayer) Perillyl alcohol (DORBioPharma) Pump inhibitors CBT-1 (CBA Pharma) Zosuquidartrihydrochloride Tariquidar (Xenova) (Eli Lilly) MS-209 (Schering AG)Biricodar dicitrate (Vertex) Histone acetyl Tacedinaline (Pfizer)Pivaloyloxymethyl butyrate transferase SAHA (Aton Pharma) (Titan)inhibitors MS-275 (Schering AG) Depsipeptide (Fujisawa)Metalloproteinase Neovastat (Aeterna CMT -3 (CollaGenex) inhibitorsLaboratories) BMS-275291 (Celltech) Ribonucleoside Marimastat (BritishBiotech) Tezacitabine (Aventis) reductase Gallium maltolate (Titan)Didox (Molecules for Health) inhibitors Triapin (Vion) TNF-alphaVirulizin (Lorus Therapeutics) Revimid (Celgene) agonists/ CDC-394(Celgene) antagonists Endothelin-A Atrasentan (Abbot) YM-598(Yamanouchi) receptor antagonists ZD-4054 (AstraZeneca) Retinoic acidFenretinide (Johnson & Alitretinoin (Ligand) receptor agonists Johnson)LGD-1550 (Ligand) Immunomodulators Interferon Dexosome therapy (AnosysOncophage (Antigenics) Pentrix (Australian Cancer GMK (Progenics)Technology) Adenocarcinoma vaccine JSF-154 (Tragen) (Biomira) Cancervaccine (Intercell) CTP-37 (AVI BioPharma) Norelin (Biostar) JRX-2(Immuno-Rx) BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics)Synchrovax vaccines (CTL !3-Alethin (Dovetail) Immuno) CLL-Thera(Vasogen) Melanoma vaccine (CTL Immuno) p21-RAS vaccine (GemVax)Hormonal and Oestrogens Prednisone antihormonal Conjugated oestrogensMethylprednisolone agents Ethynyloestradiol PrednisoloneChlorotrianisene Aminoglutethimide Idenestrol LeuprolideHydroxyprogesterone caproate Goserelin Medroxyprogesterone LeuporelinTestosterone Bicalutamide Testosterone propionate FlutamideFluoxymesterone Octreotide Methyltestosterone NilutamideDiethylstilbestrol Mitotan Megestrol P-04 (Novogen) Tamoxifen2-Methoxyoestradiol Toremofin (EntreMed) Dexamethasone Arzoxifen (EliLilly) Photodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbidagents Theralux (Theratechnologies) (Yeda) Motexafin-GadoliniumLutetium-Texaphyrin (Pharmacyclics) (Pharmacyclics) Hypericin Tyrosinekinase Imatinib (Novartis) Kahalide F (PharmaMar) inhibitors LeflunomideCEP- 701 (Cephalon) (Sugen/Pharmacia) CEP-751 (Cephalon) ZDI839(AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene Science) PKC412(Novartis) Canertjnib (Pfizer) Phenoxodiol O Squalamine (Genaera)Trastuzumab (Genentech) SU5416 (Pharmacia) C225 (ImClone) SU6668(Pharmacia) rhu-Mab (Genentech) ZD4190 (AstraZeneca) MDX-H210 (Medarex)ZD6474 (AstraZeneca) 2C4 (Genentech) Vatalanib (Novartis) MDX-447(Medarex) PKI166 (Novartis) ABX-EGF (Abgenix) GW2016 (GlaxoSmithKline)IMC-1C11 (ImClone) EKB-509 (Wyeth) EKB-569 (Wyeth) Various agentsSR-27897 (CCK-A inhibitor, BCX-1777 (PNP inhibitor, Sanofi-Synthelabo)BioCryst) Tocladesine (cyclic AMP Ranpirnase (ribonuclease agonist,Ribapharm) stimulant, Alfacell) Alvocidib (CDK inhibitor, Galarubicin(RNA synthesis Aventis) inhibitor, Dong-A) CV-247 (COX-2 inhibitor, IvyTirapazamine (reducing agent, Medical) SRI International) P54 (COX-2inhibitor, N-Acetylcysteine Phytopharm) (reducing agent, Zambon)CapCell ™ (CYP450 R-Flurbiprofen (NF-kappaB stimulant, Bavarian Nordic)inhibitor, Encore) GCS-IOO (gal3 antagonist, 3CPA (NF-kappaB inhibitor,GlycoGenesys) Active Biotech) G17DT immunogen Seocalcitol (vitamin D(gastrin inhibitor, Aphton) receptor agonist, Leo) Efaproxiral(oxygenator, Allos 131-I-TM-601 (DNA Therapeutics) antagonist,TransMolecular) PI-88 (heparanase inhibitor, Eflornithin (ODC inhibitor,ILEX Progen) Oncology) Tesmilifen (histamine Minodronic acid antagonist,YM (osteoclast inhibitor, BioSciences) Yamanouchi) Histamine (histamineH2 Indisulam (p53 stimulant, receptor agonist, Maxim) Eisai) Tiazofurin(IMPDH inhibitor, Aplidin (PPT inhibitor, Ribapharm) PharmaMar)Cilengitide (integrin Rituximab (CD20 antibody, antagonist, Merck KGaA)Genentech) SR-31747 (IL-1 antagonist, Gemtuzumab (CD33Sanofi-Synthelabo) antibody, Wyeth Ayerst) CCI-779 (mTOR kinase PG2(haematopoiesis inhibitor, Wyeth) promoter, Pharmagenesis) Exisulind(PDE-V inhibitor, Immunol ™ (triclosan Cell Pathways) mouthwash, Endo)CP-461 (PDE-V inhibitor, Cell Triacetyluridine (uridine Pathways)prodrug, Wellstat) AG-2037 (GART inhibitor, SN-4071 (sarcoma agent,Pfizer) Signature BioScience) WX-UK1 TransMID-107 ™ (plasminogenactivator (immunotoxin, KS Biomedix) inhibitor, Wilex) PCK-3145(apoptosis PBI-1402 (PMN stimulant, promoter, Procyon) ProMeticLifeSciences) Doranidazole (apoptosis Bortezomib (proteasome promoter,Pola) inhibitor, Millennium) CHS-828 (cytotoxic agent, SRL-172 (T-cellstimulant, Leo) SR Pharma) Trans-retinic acid TLK-286 (glutathione-S(differentiator, NIH) transferase inhibitor, Telik) MX6 (apoptosispromoter, PT-100 (growth factor agonist, MAXIA) Point Therapeutics)Apomine (apoptosis promoter, Midostaurin (PKC inhibitor, ILEX Oncology)Novartis) Urocidin (apoptosis Bryostatin-1 (PKC stimulant promoter,Bioniche) GPC Biotech) Ro-31-7453 (apoptosis CDA-II (apoptosis promoter,promoter, La Roche) Everlife) Brostallicin (apoptosis SDX-101 (apoptosispromoter, Pharmacia) promoter, Salmedix) Ceflatonin (apoptosis promoter,ChemGenex)

A combined treatment of this type can be achieved with the aid ofsimultaneous, consecutive or separate dispensing of the individualcomponents of the treatment. Combination products of this type employthe compounds according to the invention.

Assays

The compounds of the formula I described in the examples were tested bythe assays described below and were found to have kinase inhibitoryactivity. Other assays are known from the literature and could readilybe performed by the person skilled in the art (see, for example,Dhanabal et al., Cancer Res. 59:189-197; Xin et al., J. Biol. Chem.274:9116-9121; Sheu et al., Anticancer Res. 18:4435-4441; Ausprunk etal., Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. Cancer Inst.52:413-427; Nicosia et al., In Vitro 18:538-549).

Measurement of Met Kinase Activity

According to the manufacturer's data (Met, active, upstate, catalogueNo. 14-526), Met kinase is expressed for the purposes of proteinproduction in insect cells (Sf21; S. frugiperda) and subsequentaffinity-chromatographic purification as “N-terminal 6His-tagged”recombinant human protein in a baculovirus expression vector.

The kinase activity can be measured using various available measurementsystems. In the scintillation proximity method (Sorg et al., J. ofBiomolecular Screening, 2002, 7, 11-19), the flashplate method or thefilter binding test, the radioactive phosphorylation of a protein orpeptide as substrate is measured using radioactively labelled ATP(³²P-ATP, ³³P-ATP). In the case of the presence of an inhibitorycompound, a reduced radioactive signal, or none at all, can be detected.Furthermore, homogeneous time-resolved fluorescence resonance energytransfer (HTR-FRET) and fluoroescence polarisation (FP) technologies canbe used as assay methods (Sills et al., J. of Biomolecular Screening,2002, 191-214),

Other non-radioactive ELISA assay methods use specificphospho-antibodies (phospho-ABs). The phospho-antibody only binds thephosphorylated substrate. This binding can be detected bychemiluminescence using a second peroxidase-conjugated antibody (Ross etal., 2002, Biochem. J.).

Flashplate Method (Met Kinase)

The test plates used are 96-well Flashplate^(R) micro titre plates fromPerkin Elmer (Cat. No. SMP200). The components of the kinase reactiondescribed below are pipetted into the assay plate. The Met kinase andthe substrate poly Ala-Glu-Lys-Tyr, (pAGLT, 6:2:5:1), are incubated for3 hrs at room temperature with radioactively labelled ³³P-ATP in thepresence and absence of test substances in a total volume of 100 μl. Thereaction is terminated using 150 μl of a 60 mM EDTA solution. Afterincubation for a further 30 min at room temperature, the supernatantsare filtered off with suction, and the wells are washed three times with200 μl of 0.9% NaCl solution each time. The measurement of the boundradioactivity is carried out by means of a scintillation measuringinstrument (Topcount NXT, Perkin-Elmer).

The full value used is the inhibitor-free kinase reaction. This shouldbe approximately in the range 6000-9000 cpm. The pharmacological zerovalue used is staurosporin in a final concentration of 0.1 mM. Theinhibitory values (IC50) are determined using the RS1_MTS program.

Kinase reaction conditions per well:

30 μl of assay buffer

10 μl of substance to be tested in assay buffer with 10% of DMSO

10 μl of ATP (final concentration 1 μM cold, 0.35 μCi of ³³P-ATP)

50 μl of Met kinase/substrate mixture in assay buffer;

-   -   (10 ng of enzyme/well, 50 ng of pAGLT/well)    -   Solutions used:        -   Assay buffer:    -   50 mM HEPES        -   3 mM magnesium chloride        -   3 μM sodium orthovanadate        -   3 mM manganese(II) chloride        -   1 mM dithiothreitol (DTT)    -   pH=7.5 (to be set using sodium hydroxide)        -   Stop solution:    -   60 mM Titriplex III (EDTA)        -   ³³P-ATP: Perkin-Elmer;        -   Met kinase: Upstate, Cat. No. 14-526, Stock 1 μg/10 μl;            spec. activity 954 U/mg;        -   Poly-Ala-Glu-Lys-Tyr, 6:2:5:1: Sigma Cat. No. P1152

In-vivo Tests

Experimental procedure: Female Balb/C mice (breeder: Charles River Wiga)were 5 weeks old on arrival. They were acclimatised to our keepingconditions for 7 days. Each mouse was subsequently injectedsubcutaneously in the pelvic area with 4 million TPR-Met/NIH3T3 cells in100 μl of PBS (without Ca++ and Mg++). After 5 days, the animals wererandomised into 3 groups, so that each group of 9 mice had an averagetumour volume of 110 μl (range: 55-165). 100 μl of vehicle (0.25%methylcellulose/100 mM acetate buffer, pH 5.5) were administered dailyto the control group, and 200 mg/kg of “A56” or “A91” dissolved in thevehicle (volume likewise 100 μl/animal) were administered daily to thetreatment groups, in each case by gastric tube. After 9 days, thecontrols had an average volume of 1530 μl and the experiment wasterminated.

Measurement of the tumour volume: The length (L) and breadth (B) weremeasured using a Vernier calliper, and the tumour volume was calculatedfrom the formula L×B×B/2.

Keeping conditions: 4 or 5 animals per cage, feeding with commercialmouse food (Sniff).

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, to values between 2 and 10, depending onthe constitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the residue is purifiedby chromatography on silica gel and/or by crystallisation. Rf values onsilica gel; eluent:ethyl acetate/methanol 9:1;

melting point m.p. in ° C.

Mass spectrometry (MS): EI (electron impact ionisation) M⁺

-   -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺

APCI-MS (atmospheric pressure chemical ionisation-mass spectrometry)(M+H)⁺.

Mass spectrometry (MS): EI (electron impact ionisation) M⁺

-   -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺

APCI-MS (atmospheric pressure chemical ionisation-mass spectrometry)(M+H)⁺.

HPLC Methods:

Method A: gradient: 4.5 min/fl.: 3 ml/min 99:01-0:100

-   -   water+0.1% (vol.) of TFA:acetonitrile+0.1% (vol.) of TFA    -   0.0 to 0.5 min: 99:01    -   0.5 to 3.5 min: 99:01→0:100    -   3.5 to 4.5 min: 0:100    -   Column: Chromolith SpeedROD RP18e 50-4.6    -   Wavelength: 220 nm

Method B: gradient: 4.2 min/flow: 2 ml/min 99:01-0:100

-   -   water+0.1% (vol.) of TFA:acetonitrile 0.1% (vol.) of TFA    -   0.0 to 0.2 min: 99:01    -   0.2 to 3.8 min: 99:01→0:100    -   3.8 to 4.2 min: 0:100    -   Column: Chromolith Performance RP18e; 100 mm long, internal        diameter 3 mm    -   Wavelength: 220 nm

Retention time Rt. in minutes [min].

EXAMPLE 1

The preparation of2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-phenylamino-2H-pyridazin-3-one(“A1”) is carried out analogously to the following scheme

1.1 1382 g (10.0 mol) of potassium carbonate are added in portions withstirring to a suspension, kept at 30° C., of 500 g (3.40 mol) of3-cyanobenzoic acid in 8 l of methanol. 695 g (10.0 mol) ofhydroxylammonium chloride are subsequently added in small portions at aninternal temperature of 40-45° C. The reaction mixture is then heated atthe boil for 15 hours. The reaction mixture is evaporated in vacuo, theresidue is dissolved in water and acidified using 37% aqueoushydrochloric acid. The precipitate formed is filtered off with suction,washed with water and dried in vacuo: 3-(N-hydroxycarbamimidoyl)benzoicacid as colourless crystals; ESI 181.

1.2 A mixture of 614 g (3.41 mol) of 3-(N-hydrocarbamimidoyl)benzoicacid, 756 ml (8.0 mol) of acetic anhydride and 2 l of acetic acid isheated at a temperature of 118° C. for 14 hours. The reaction mixture iscooled to 6° C. and filtered off with suction. The residue is taken upin 2 l of water, filtered off with suction and washed well with water.The residue is recrystallised from ethanol/water:3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid as colourless crystals;m.p. 225°; ESI 205.

1.3 7.83 ml (147 mmol) of concentrated sulfuric acid are added to asuspension of 30.0 g (147 mmol) of3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid in 150 ml of methanol, andthe mixture is heated at the boil for 18 hours. The reaction mixture iscooled in an ice bath, water is added, and the reaction mixture isfiltered off with suction and washed well with water: methyl3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate as colourless crystals; ESI219.

1.4 150 ml of acetic acid, 150 ml of water and 50 g of water-moist Raneynickel are added to a solution of 327 g (1.47 mol) of methyl3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate in 3 l of methanol, and themixture is hydrogenated for 18 hours at room temperature and atmosphericpressure. The catalyst is filtered off, and the filtrate is evaporated.The residue is taken up in tert-butyl methyl ether, heated to the boiland filtered off with suction. The residue is dried in vacuo:3-methoxycarbonylbenzamidinium acetate as colourless crystals; ESI 179.

1.5 2.2 l of a freshly prepared 1.5 M sodium methoxide solution areadded dropwise with stirring to a suspension of 259 g (1.09 mol) of3-methoxycarbonylbenzamidinium acetate and 528 g (1.08 mol) of({2-dimethylamino-1-[dimethylimmoniomethyl]vinylamino}methylene)dimethylammoniumdihexafluorophosphate (prepared in accordance with C. B. Dousson et al.,Synthesis 2005, 1817) in 1 l of methanol. The reaction mixture is thenwarmed to 60° C. over the course of 40 min and kept at this temperaturefor 30 min. The reaction mixture is then cooled to room temperature,diluted with 10 l of dichloromethane and washed three times with 5 l ofwater each time. The organic phase is dried over sodium sulfate andevaporated. The residue is recrystallised from ethyl acetate: methyl3-[5-(dimethylaminomethyleneamino)pyrimidin-2-yl]benzoate as beigecrystals; m.p. 140°, ESI 285.

1.6 160 ml (2.88 mol) of concentrated sulfuric acid are added to asuspension of 103.5 g (364 mmol) of methyl3-[5-(dimethylaminomethyleneamino)pyrimidin-2-yl]benzoate in 1.3 l ofwater, and the mixture is heated at the boil for 4 hours. The reactionmixture is cooled to room temperature, diluted with water and filteredoff with suction. The residue is washed with water and dried in vacuo:3-(5-hydroxypyrimidin-2-yl)benzoic acid as brownish crystals; ESI 217.

1.7 32.7 ml (445 mmol) of thionyl chloride are added to a suspension of88.0 g (366 mmol) of 3-(5-hydroxypyrimidin-2-yl)benzoic acid in 1.4 l ofmethanol, and the mixture is heated at 80° C. for 2 hours. 20 ml (276mmol) of thionyl chloride and, after 2 hours, again 10 ml (138 mmol) ofthionyl chloride are then added. After each addition, the reactionmixture is stirred at 80° C. for 2 hours. The reaction mixture isevaporated to a volume of about 300 ml in vacuo. The precipitate formedis filtered off and dried in vacuo: methyl3-(5-hydroxypyrimidin-2-yl)benzoate as brownish crystals; ESI 231.

1.8 A solution, kept under nitrogen, of 6.1 g (26.5 mmol) ofmethyl-(5-hydroxypyrimidin-2-yl)benzoate, 10.5 g (39.8 mmol) oftriphenylphosphine and 4.76 ml (39.8 mmol) of3-(dimethylamino)-1-propanol in 200 ml of THF is cooled in an ice bath,and 8.21 ml (39.8 mmol) of diisopropyl azodicarboxylate are slowly addeddropwise with stirring. After stirring at room temperature for 2 hours,the reaction mixture is evaporated in vacuo. The residue is partitionedbetween dichloromethane and saturated aqueous potassium hydrogensulfatesolution. The aqueous phase is separated off, brought to a pH of 12using saturated aqueous sodium hydroxide solution and extracted twicewith dichloromethane. The organic phase is dried over sodium sulfate andevaporated. The residue is chromatographed on a silica-gel column withdichloromethane/methanol as eluent: methyl3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzoate as colourlesscrystals; ESI 316.

1.9 200 ml of a 1 M solution of diisobutylaluminium hydride in THF areadded dropwise with stirring to a solution, kept under nitrogen, of 12.6g (40.0 mmol) of methyl3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzoate in 200 ml of THF.After the mixture has been stirred at room temperature for 1 hour, 10 mlof a saturated aqueous sodium sulfate solution are added dropwise. Theprecipitate formed is filtered off with suction and washed withdichloromethane. The filtrate is dried over sodium sulfate andevaporated. The residue is taken up in a mixture of diethyl ether andpetroleum ether. The precipitate formed is filtered off with suction,washed with petroleum ether and dried in vacuo:{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]phenyl}methanol ascolourless crystals; m.p. 95-97°; ESI 288.

1.10 14 ml of water are added to a solution of 2.14 g (10.0 mmol) of3-chloro-6-anilinopyridazine (prepared in accordance with F. Yoneda etal., Chem. Pharm. Bull. 11, 740-744, 1963) in 14 ml of formic acid, andthe mixture is stirred at 100° C. for 11 days. The reaction mixture iscooled to room temperature. The precipitate formed is filtered off withsuction, washed with water and dried in vacuo:6-phenylamino-2H-pyridazin-3-one as yellowish crystals; ESI 188.

1.11 122 mg (0.65 mmol) of 6-phenylamino-2H-pyridazin-3-one and 199 mg(0.75 mmol) of triphenylphosphine are added to a solution of 144 mg(0.50 mmol) of{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]-phenyl}methanol in 5 ml ofTHF. The suspension formed is cooled in an ice bath, and 155 μl (0.75mmol) of diisopropyl azodicarboxylate are slowly added dropwise. Afterstirring at room temperature for 2 hours, the reaction mixture isevaporated, and the residue is chromatographed on a silica-gel columnwith dichloromethane/methanol as eluent. The product-containingfractions are combined, evaporated and crystallised using tert-butylmethyl ether:2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-phenylamino-2H-pyridazin-3-oneas yellowish crystals; ESI 457

¹H-NMR (d₆-DMSO): δ [ppm] 1.91 (quintet, J=6.6 Hz, 2H), 2.19 (s, 6H),2.41 (t, J=6.9 Hz, 2H), 4.23 (t, J=6.5 Hz, 2H), 5.23 (s, 2H), 6.87 (t,J=7.5 Hz, 1H), 6.95 (d, J=10 Hz, 1H), 7.20 (m, 3H), 7.49 (m, 4H), 8.23(dt, J₁=6.9 Hz, J₂=1.5 Hz, 1H), 8.35 (s, 1H), 8.64 (s, 2H), 9.02 (bs,1H).

EXAMPLE 2

The preparation of6-phenylamino-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one(“A2”) is carried out analogously to the following scheme

2.1 A solution of 70.0 g (660 mmol) of sodium carbonate in 325 ml ofwater is added to a solution, kept under nitrogen, of 95.0 g (332 mmol)of 5-bromo-2-iodopyrimidine in 325 ml of toluene, and the mixture isheated to 80° C. 2.3 g (3.3 mmol) ofbis(triphenylphosphine)palladium(II) chloride are added, and a solutionof 50.0 g (329 mmol) of 3-(hydroxymethyl)benzeneboronic acid in 650 mlof ethanol is subsequently added dropwise. The reaction mixture isstirred at 80° C. for 18 hours. The reaction mixture is cooled to roomtemperature and filtered. 1 l of ethyl acetate and 1 l of water areadded to the filtrate. The organic phase is separated off, dried oversodium sulfate and evaporated. The residue is recrystallised from2-propanol: [3-(5-bromopyrimidin-2-yl)phenyl]methanol as pale-yellowcrystals; ESI 265,267.

2.2 4.25 g (20.0 mmol) of tripotassium phosphate trihydrate are added toa suspension, kept under nitrogen, of 2.65 g (10.0 mmol) of[3-(5-bromopyrimidin-2-yl)phenyl]methanol and 3.96 g (10.5 mmol) oftert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate(prepared in accordance with WO 2007/066187), and the mixture is heatedto 80° C. 843 mg of bis(triphenylphosphine)palladium(II) chloride areadded, and the reaction mixture is stirred at 80° C. for 18 hours. Thereaction mixture is cooled to room temperature, water anddichloromethane are added, and the reaction mixture is filtered. Theorganic phase of the filtrate is separated off, dried over sodiumsulfate and evaporated. The residue is chromatographed on a silica-gelcolumn with dichloromethane/methanol: tert-butyl4-{4-[2-(3-hydroxymethylphenyl)pyrimidin-5-yl]pyrazol-1-yl}piperidine-1-carboxylateas colourless crystals; ESI 436.

2.3 A solution of 196 mg (1.05 mmol) of6-phenylamino-2H-pyridazin-3-one, 592 mg (1.36 mmol) of tert-butyl4-{4-[2-(3-hydroxymethylphenyl)pyrimidin-5-yl]pyrazol-1-yl}piperidine-1-carboxylateand 412 mg (1.57 mmol) of triphenylphosphine in 10 ml of THF is cooledin an ice bath, and 311 μl (1.57 mmol) of diisopropyl azodicarboxylateare added dropwise. The reaction mixture is stirred at room temperaturefor 18 hours. The mixture is evaporated, and the residue ischromatographed on a silica-gel column with dichloromethane/methanol aseluent: tert-butyl4-(4-{2-[3-(6-oxo-3-phenylamino-6H-pyridazin-1-ylmethyl)phenyl]pyrimidin-5-yl}pyrazol-1-yl)piperidine-1-carboxylateas yellow crystals; ESI 605.

2.4 A suspension of 341 mg (0.564 mmol) of tert-butyl4-(4-{2-[3-(6-oxo-3-phenylamino-6H-pyridazin-1-ylmethyl)phenyl]pyrimidin-5-yl}pyrazol-1-yl)piperidine-1-carboxylatein a mixture of 5 ml of 10% HCl in dioxane and 1 ml of methanol isbriefly heated to the boil. The mixture is allowed to cool, theprecipitate formed is filtered off with suction and washed withtert-butyl methyl ether:6-phenylamino-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-onehydrochloride as yellowish crystals; ESI 505;

¹H-NMR (d₆-DMSO): δ [ppm] 2.25 (m, 4H), 3.10 (m, 2H), 3.39 (m, 2H), 4.57(m, 1H), 5.23 (s, 2H), 6.86 (t, J=7.5 Hz, 1H), 6.95 (d, J=10 Hz, 1H),7.20 (t, J=7.5 Hz, 2H), 7.34 (d, J=10 Hz, 1H), 7.53 (m, 4H), 8.18 (s,1H), 8.32 (m, 1H), 8.43 (s, 1H), 8.52 (s, 1H), 9.17 (m, 1H), 9.18 (s,2H), 9.33 (bs, 1H), 9.42 (m, 1H).

EXAMPLE 3

The preparation of6-phenoxy-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one(“A3”) is carried out analogously to the following scheme

3.1 21 ml of water are added to a solution of 3.10 g (15.0 mmol) of3-chloro-6-phenoxypyridazine in 21 ml of formic acid, and the mixture isheated at 95° C. for 85 hours. The reaction mixture is cooled andbrought to a pH of 6 using 23% aqueous sodium hydroxide solution. Theprecipitate formed is filtered off with suction, washed with water anddried in vacuo, giving 6-phenoxy-2H-pyridazin-3-one as colourlesscrystals; ESI 189.

3.2 116 g (438 mmol) of [3-(5-bromopyrimidin-2-yl)phenyl]methanol isadded in portions with stirring to 159 ml (2.19 mol) of thionyl chloridekept at 30° C. The reaction solution formed is stirred at roomtemperature for 18 hours. The reaction mixture is evaporated. Theresidue is taken up in toluene and re-evaporated. This procedure isrepeated three times. The residue is recrystallised from toluene:5-bromo-2-(3-chloromethylphenyl)pyrimidine as colourless crystals; m.p.148°; ESI 283, 285, 286.

3.3 2.59 g (9.14 mmol) of 5-bromo-2-(3-chloromethylphenyl)pyrimidine and2.84 g (8.70 mmol) of caesium carbonate are added to a suspension of1.64 g (8.70 mmol) of 6-phenoxy-2H-pyridazin-3-one in 17.5 ml of DMF,and the mixture is stirred at room temperature for 18 hours. Water isadded to the reaction mixture. The precipitate formed is filtered offwith suction, washed with water and dried in vacuo, giving2-[3-(5-bromopyrimidin-2-yl)benzyl]-6-phenoxy-2H-pyridazin-3-one ascolourless crystals; ESI 435, 437.

3.4 A solution of 10.0 g (50.5 mmol) of pinacolyl pyrazole-4-boronate isdissolved in 100 ml of acetonitrile, and 17.5 g (101 mmol) ofN-(2-chloroethyl)pyrrolidine hydrochloride and 49.4 g (152 mmol) ofcaesium carbonate are added. The suspension formed is stirred at roomtemperature for 18 hours. The reaction mixture is filtered off withsuction and washed with acetonitrile. The filtrate is evaporated andpartitioned between ethyl acetate and saturated sodium chloridesolution. The organic phase is dried over sodium sulfate and evaporated:1-(2-pyrrolidin-1-ylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleas pale-orange oil, which gradually crystallises;

¹H-NMR (d₆-DMSO): δ [ppm] 1.25 (s, 12H), 1.65 (m, 4H), 2.44 (m, 4H),2.79 (t, J=6.8 Hz, 2H), 4.21 (t, J=6.8 Hz, 2H), 7.56 (s, 1H), 7.93 (s,1H).

3.5 A suspension of 218 mg (0.50 mmol) of2-[3-(5-bromopyrimidin-2-yl)benzyl]-6-phenoxy-2H-pyridazin-3-one, 251 mg(0.75 mmol) of1-(2-pyrrolidin-1-ylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(content 87%) and 230 mg (1.00 mmol) of tripotassium phosphatetrihydrate in 2 ml of 1,2-dimethoxyethane and 1 ml of DMF is heated to85° C. under nitrogen. 35.0 mg (0.05 mmol) ofbis(triphenylphosphine)palladium(II) chloride and 9 μl (0.07 mmol) oftriethylamine are then added and stirred at 85° C. for 42 hours. Thereaction mixture is partitioned between THF and saturated sodiumchloride solution. The organic phase is dried over sodium sulfate,evaporated and chromatographed on a silica-gel column withmethanol/tert-butyl ether as eluent, giving6-phenoxy-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}benzyl)-2H-pyridazin-3-oneas yellowish amorphous material; ESI 520.

¹H-NMR (d₆-DMSO): δ [ppm] 1.68 (m, 4H), 2.89 (t, J=6.3 Hz, 2H), 3.32 (m,4H), 4.28 (t, J=6.6 Hz, 2H), 5.15 (s, 2H), 7.15 (d, J=9.6 Hz, 1H), 7.20(m, 3H), 7.37 (m, 3H), 7.45 (d, J=9.6 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H),8.12 (s, 1H), 8.29 (bs, 1H), 8.31 (d, J=8.1 Hz, 1H), 8.47 (s, 1H), 9.16(s, 2H).

The following compound is prepared analogously:

tert-butyl4-(4-{2-[3-(6-oxo-3-phenoxy-6H-pyridazin-1-ylmethyl)phenyl]pyrimidin-5-yl}pyrazol-1-yl)piperidine-1-carboxylate.

This is converted into6-phenoxy-2-{3-[5(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-onehydrochloride (“A4”) analogously to Example 2 using dioxane/HCl.

The following compounds are obtained analogously to Example 3

The compound2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-6-phenoxy-2H-pyridazin-3-one(“A7”) is prepared in accordance with the following synthesis scheme:

Preparation of1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazine-3-carboxamide(“A8”)

261 mg of polymer-bound triphenylphosphine and 184 mg (0.783 mmol) ofdi-tert-butyl azodicarboxylate are added to a solution of 72.6 mg (0.522mmol) of 6-oxo-1,6-dihydropyridazine-3-carboxamide (preparation inaccordance with King, McMillan, J. Am, Chem. Soc. 74, p. 3222, 1952) and150 mg (0.522 mmol) of{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]-phenyl}methanol amide in 3ml of THF and 1 ml of DMF. The reaction mixture is stirred at roomtemperature for 18 hours, then filtered through kieselguhr, and thefiltrate is evaporated. The residue is purified by preparative HPLC:1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazine-3-carboxamidetrifluoroacetate as colourless oil; ESI 409;

¹H-NMR (d₆-DMSO): δ [ppm] 2.15 (m, 2H), 2.83 (d, J=4 Hz, 6H), 3.25 (m,2H), 4.28 (t, J=6 Hz, 2H), 5.37 (s, 2H), 7.05 (d, J=9.5 Hz, 1H), 7.47(t, J=7.5 Hz, 1H), 7.54 (d, J=8 Hz, 1H), 7.70 (bs, 1H), 7.88 (d, J=9.5Hz, 1H), 7.97 (bs, 1H), 8.24 (d, J=7.5 Hz, 1H), 8.29 (bs, 1H), 8.65 (s,2H), 9.39 (bs, 1H).

Pharmacological Data

Met Kinase Inhibition

TABLE 1 IC₅₀ IC₅₀ Compound No. (enzyme) (cell) “A1” A B “A2” A B “A3” AB “A4” B B “A8” B B IC₅₀: 1 nM-0.1 μM = A 0.1 μM-10 μM = B >10 μM = C

The following examples relate to medicaments:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

The invention claimed is:
 1. A compound of formula I

in which D denotes a five- or six-membered unsaturated or aromaticheterocycle having 1 to 3 N, O and/or S atoms, which may beunsubstituted or mono-, di- or trisubstituted by Hal and/or A, R¹denotes OH, OA, O[C(R⁵)₂]_(n)Ar, O[C(R⁵)₂]_(n)Het, O[C(R⁵)₂]_(p)N(R⁵)₂,N(R⁵)₂, NR⁵[C(R⁵)₂]_(n)Ar, NR⁵[C(R⁵)₂]_(n)Het, NR⁵[C(R⁵)₂]_(p)N(R⁵)₂,COOR⁵, CON(R⁵)₂, CONR⁵[C(R⁵)₂]_(p)N(R⁵)₂, CONR⁵[C(R⁵)₂]_(p)OR⁵,CONR⁵[C(R⁵)₂]_(n)Het, COHet or COA, R² denotes H, A, Hal, OH, OA,N(R⁵)₂, N═CR⁵N(R⁵)₂, SR⁵, NO₂, CN, COOR⁵, CON(R⁵)₂, NR⁵COA, NR⁵SO₂A,SO₂N(R⁵)₂, S(O)_(m)A, [C(R⁵)₂]_(n)N(R⁵)₂, [C(R⁵)₂]_(n)Het,O[C(R⁵)₂]_(p)N(R⁵)₂, O[C(R⁵)₂]_(n)Het, S[C(R⁵)₂]_(p)N(R⁵)₂,S[C(R⁵)₂]_(n)Het, NR⁵[C(R⁵)₂]_(p)N(R⁵)₂, —NR⁵[C(R⁵)₂]_(n)Het,NHCON(R⁵)₂, NHCONH[C(R⁵)₂]_(p)N(R⁵)₂, NHCONH[C(R⁵)₂]_(n)Het,NHCO[C(R⁵)₂]_(p)—N(R⁵)₂, NHCO[C(R⁵)₂]_(n)Het, CON(R⁵)₂,CONR⁵[C(R⁵)₂]_(p)N(R⁵)₂, CONR⁵[C(R⁵)₂]_(n)Het, COHet, COA,O[C(R⁵)₂]_(n)NR⁵COZ, O[C(R⁵)₂]_(n)NR²COHet¹,O[C(R⁵)₂]_(n)Cyc[C(R⁵)₂]_(n)N(R⁵)₂, O[C(R⁵)₂]_(n)Cyc[C(R⁵)₂]_(n)OR⁵,O[C(R⁵)₂]_(n)Cyc[C(R⁵)₂]_(n)Het¹,

 O[C(R⁵)₂]_(n)CR⁵(NR⁵)₂COOR⁵, O[C(R⁵)₂]_(n)NR⁵CO[C(R⁵)₂]_(n)NR⁵COA,O[C(R⁵)₂]_(n)NR⁵COOA, O[C(R⁵)₂]_(n)CO—NR⁵-A,O[C(R⁵)₂]_(n)CO—NR⁵—O[C(R⁵)₂]_(n)Het¹, O[C(R⁵)₂]_(n)CONH₂,O[C(R⁵)₂]_(n)CONHA, O[C(R⁵)₂]_(n)CONA₂,O[C(R⁵)₂]_(n)CO—NR⁵—[C(R²)₂]_(n)N(R⁵)₂ or OCOA, Z denotesCR⁵(NR⁵)₂CR⁵(OR⁵)A, R³ denotes H or A, R⁴ denotes H, A or Hal, R⁵denotes H or A′, A denotes unbranched or branched alkyl having 1-6 Catoms, in which 1-5 H atoms may be replaced by F, and/or in which one ortwo non-adjacent CH₂ groups may be replaced by O, cyclic alkyl having3-7 C atoms, in which 1-7 H atoms may be replaced by OH, F, Cl and/orBr, A′ denotes unbranched or branched alkyl having 1-6 C atoms, in which1-5 H atoms may be replaced by F, Cyc denotes cycloalkylene having 3-7 Catoms, Ar denotes phenyl, naphthyl or biphenyl, each of which isunsubstituted or mono-, di- or trisubstituted by Hal, A, OR⁵, N(R⁵)₂,SR⁵, NO₂, CN, COOR⁵, CON(R⁵)₂, NR⁵COA, NR⁵SO₂A, SO₂N(R⁵)₂, S(O)_(m)A,CO-Het¹, [C(R⁵)₂]_(n)N(R⁵)₂, [C(R⁵)₂]_(n)Het¹, O[C(R⁵)₂]_(p)—N(R⁵)₂,O[C(R⁵)₂]_(n)Het¹, NHCOOA, NHCON(R⁵)₂, NHCOO[C(R⁵)₂]_(p)N(R⁵)₂,NHCOO[C(R⁵)₂]_(n)Het¹, NHCONH[C(R⁵)₂]_(p)N(R⁵)₂, NHCONH[C(R⁵)₂]_(n)Het¹,OCONH[C(R⁵)₂]_(p)N(R⁵)₂ and/or OCONH[C(R⁵)₂]_(n)Het¹, Het denotes amono-, bi- or tricyclic saturated, unsaturated or aromatic heterocyclehaving 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-,di- or trisubstituted by Hal, A, OR⁵, N(R⁵)₂, SR⁵, NO₂, CN, COOR⁵,CON(R⁵)₂, NR⁵COA, NR⁵SO₂A, SO₂N(R⁵)₂, S(O)_(m)A, CO-Het¹,[C(R⁵)₂]_(n)N(R⁵)₂, [C(R⁵)₂]_(n)Het¹, O[C(R⁵)₂]_(p)N(R⁵)₂,O[C(R⁵)₂]_(n)Het¹, NHCOOA, NHCON(R⁵)₂, NHCOO[C(R⁵)₂]_(p)N(R⁵)₂,NHCOO[C(R⁵)₂]_(n)Het¹, NHCONH[C(R⁵)₂]_(p)N(R⁵)₂, NHCONH[C(R⁵)₂]_(n)Het¹,OCONH[C(R⁵)₂]_(p)N(R⁵)₂, OCONH[C(R⁵)₂]_(n)Het¹, CO-Het¹, CHO, COA, ═S,═NH, ═NA and/or ═O (carbonyl oxygen), Het¹ denotes a monocyclicsaturated heterocycle having 1 to 2 N and/or O atoms, which may be mono-or disubstituted by A, OA, OH, Hal and/or ═O (carbonyl oxygen), Haldenotes F, Cl, Br or I, m denotes 0, 1 or 2, n denotes 0, 1, 2, 3 or 4,p denotes 2, 3, 4, 5, or 6, q denotes 1, 2, 3, 4 or 5, apharmaceutically usable salt, tautomer or stereoisomer thereof, or amixture thereof in all ratios.
 2. The compound according to claim 1 inwhich R¹ denotes OH, OA, O[C(R⁵)₂]_(n)Ar, N(R⁵)₂, CON(R⁵)₂ orNR⁵[C(R⁵)₂]_(n)Ar, a pharmaceutically usable salt, tautomer orstereoisomer thereof, or a mixture thereof in all ratios.
 3. Thecompound according to claim 1 in which R² denotes [C(R⁵)₂]_(n)Het orO[C(R⁵)₂]_(p)N(R⁵)₂, a pharmaceutically usable salt, tautomer orstereoisomer thereof, or a mixture thereof in all ratios.
 4. Thecompound according to claim 1 in which R³ denotes H or methyl, apharmaceutically usable salt, tautomer or stereoisomer thereof, or amixture thereof in all ratios.
 5. The compound according to claim 1 inwhich Ar denotes phenyl, a pharmaceutically usable salt, tautomer orstereoisomer thereof, or a mixture thereof in all ratios.
 6. Thecompound according to claim 1 in which R⁴ denotes H, a pharmaceuticallyusable salt, tautomer or stereoisomer thereof, or a mixture thereof inall ratios.
 7. The compound according to claim 1 in which Het denotes amonocyclic aromatic heterocycle having 1 to 4 N, O and/or S atoms, whichmay be unsubstituted or mono- or disubstituted by [C(R⁵)₂]_(n)Het¹, apharmaceutically usable salt, tautomer or stereoisomer thereof, or amixture thereof in all ratios.
 8. The compound according to claim 1 inwhich Het denotes pyrazolyl, pyridinyl, pyrimidinyl, furyl, thienyl,oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl or isoxazolyl, where theradicals may also be mono- or disubstituted by [C(R⁵)₂]_(n)Het¹, apharmaceutically usable salt, tautomer or stereoisomer thereof, or amixture thereof in all ratios.
 9. The compound according to claim 1 inwhich Het¹ denotes piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl,oxazolidinyl or imidazolidinyl, where the radicals may also be mono- ordisubstituted by ═O and/or A, a pharmaceutically usable salt, tautomeror stereoisomer thereof, or a mixture thereof in all ratios.
 10. Thecompound according to claim 1 in which D denotes thiazolediyl,thiophenediyl, furandiyl, pyrrolediyl, oxazolediyl, isoxazolediyl,oxadiazolediyl, pyrazolediyl, imidazolediyl, thiadiazolediyl,pyridazinediyl, pyrazinediyl, pyridinediyl or pyrimidinediyl, where theradicals may also be mono-, di- or trisubstituted by Hal and/or A, apharmaceutically usable salt, tautomer or stereoisomer thereof, or amixture thereof in all ratios.
 11. The compound according to claim 1 inwhich R¹ denotes OH, OA, O[C(R⁵)₂]_(n)Ar, N(R⁵)₂, CON(R⁵)₂ orNR⁵[C(R⁵)₂]_(n)Ar, R² denotes [C(R⁵)₂]_(n)Het or O[C(R⁵)₂]_(p)N(R⁵)₂, R³denotes H or methyl, R⁴ denotes H, R⁵ denotes H or A′, A denotesunbranched or branched alkyl having 1-6 C atoms, in which 1-5 H atomsmay be replaced by F, and/or in which one or two CH₂ groups may bereplaced by O, A′ denotes unbranched or branched alkyl having 1-6 Catoms, in which 1-5 H atoms may be replaced by F, Ar denotes phenyl, Hetdenotes a monocyclic aromatic heterocycle having 1 to 4 N, O and/or Satoms, which may be unsubstituted or mono- or disubstituted by[C(R⁵)₂]₁Het¹, Het¹ denotes piperidinyl, pyrrolidinyl, morpholinyl,piperazinyl, oxazolidinyl or imidazolidinyl, where the radicals may alsobe mono- or disubstituted by ═O and/or A, D denotes thiazolediyl,thiophenediyl, furandiyl, pyrrolediyl, oxazolediyl, isoxazolediyl,oxadiazolediyl, pyrazolediyl, imidazolediyl, thiadiazolediyl,pyridazinediyl, pyrazinediyl, pyridinediyl or pyrimidinediyl, where theradicals may also be mono-, di- or trisubstituted by Hal and/or A, Haldenotes F, Cl, Br or I, n denotes 0, 1, 2, 3 or 4, p denotes 2, 3, 4, 5,or 6, a pharmaceutically usable salt, tautomer or stereoisomer thereof,or a mixture thereof in all ratios.
 12. The compound according to claim1 in which R¹ denotes OH, OA, O[C(R⁵)₂]_(n)Ar, N(R⁵)₂, CON(R⁵)₂ orNR⁵[C(R⁵)₂]_(n)Ar, R² denotes [C(R⁵)₂]_(n)Het or O[C(R⁵)₂]_(p)N(R⁵)₂, R³denotes H or methyl, R⁴ denotes H, R⁵ denotes H or A′, A denotesunbranched or branched alkyl having 1-6 C atoms, in which 1-5 H atomsmay be replaced by F, and/or in which one or two CH₂ groups may bereplaced by O, A′ denotes unbranched or branched alkyl having 1-6 Catoms, Ar denotes phenyl, Het denotes pyrazolyl, pyridinyl, pyrimidinyl,furyl, thienyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl orisoxazolyl, where the radicals may also be mono- or disubstituted by[C(R⁵)₂]_(n)Het¹, Het¹ denotes piperidinyl, pyrrolidinyl, morpholinyl,piperazinyl, oxazolidinyl or imidazolidinyl, where the radicals may alsobe monosubstituted by A, D denotes thiazolediyl, thiophenediyl,furandiyl, pyrrolediyl, oxazolediyl, isoxazolediyl, oxadiazolediyl,pyrazolediyl, imidazolediyl, thiadiazolediyl, pyridazinediyl,pyrazinediyl, pyridinediyl or pyrimidinediyl, Hal denotes F, Cl, Br orI, n denotes 0, 1, 2, 3 or 4, p denotes 2, 3 or 4, a pharmaceuticallyusable salt, tautomer or stereoisomer thereof, or a mixture thereof inall ratios.
 13. The compound according to claim 1, that is No. Structureand/or name “A1”2-{3-[5-(3-Dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-phenylamino-2H-pyridazin-3-one “A2”6-Phenylamino-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A3”6-Phenoxy-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one “A4”6-Phenoxy-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A5”

“A6”

“A7” 2-[3-(5-Methyl-1,2,4-oxadiazol-3-yl)benzyl]-6-phenoxy-2H-pyridazin-3-one “A8”1-{3-[5-(3-Dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazine-3-carboxamide

a pharmaceutically usable salt, tautomer or stereoisomer thereof, or amixture thereof in all ratios.
 14. A process for the preparation of acompound of formula I according to claim 1 or a pharmaceutically usablesalt, tautomer or stereoisomer thereof, comprising a) reacting acompound of formula II

in which R¹ has the meaning indicated in claim 1, with a compound offormula III

in which D, R², R³ and R⁴ have the meanings indicated in claim 1 and Ldenotes Cl, Br, I or a free or reactive modified OH group, or b)liberating a compound of formula I from a derivative by treatment with asolvolysing or hydrogenolysing agent, and/or converting a base or acidof formula I into a salt.
 15. A pharmaceutical composition, comprisingat least one compound of formula I according to claim 1 and/or apharmaceutically usable salt, tautomer or stereoisomer thereof, or amixture thereof in all ratios, and a pharmaceutically acceptablecarrier.
 16. A pharmaceutical composition according to claim 15, furthercomprising at least one further pharmaceutically active ingredient. 17.A kit consisting of separate packs of (a) an effective amount of acompound of the formula I according to claim 1 and/or a pharmaceuticallyusable salt, stereoisomer or mixture thereof in all ratios, and (b) aneffective amount of a further pharmaceutically active ingredient.